Safe and effective method of treating psoriasis with anti-IL-23 specific antibody

ABSTRACT

A method of treating psoriasis in a patient by administering an IL-23 specific antibody, e.g., guselkumab, in a clinically proven safe and clinically proven effective amount and the patient achieves PASI90, PASI100 or IGA 0 or 1 score as measured 16, 24, 32, 40 and 48 weeks after initial treatment and the patient achieves higher efficacy than a patient treated with the secukinumab antibody.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application Provisional Ser.No. 62/769,889, filed 20 Nov. 2018, 62/796,673, filed 25 Jan. 2019,62/810,617, filed 26 Feb. 2019, 62/817,711, filed 13 Mar. 2019 and62/915,115, filed 15 Oct. 2019, the entire contents of which areincorporated herein by reference in their entireties.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

This application contains a sequence listing, which is submittedelectronically via EFS-Web as an ASCII formatted sequence listing with afile name “JBI6025USNP1Sequence Listing.txt” creation date of 18 Nov.2018, and having a size of 79,961 bytes.

FIELD OF THE INVENTION

The present invention concerns methods for treating psoriasis with anantibody that binds the human IL-23 protein. In particular, it relatesto a method of administering an anti-IL-23 specific antibody andspecific pharmaceutical compositions of an antibody, e.g., guselkumab,which is safe and effective for patients suffering from psoriasis.

BACKGROUND OF THE INVENTION

Interleukin (IL)-12 is a secreted heterodimeric cytokine comprised of 2disulfide-linked glycosylated protein subunits, designated p35 and p40for their approximate molecular weights. IL-12 is produced primarily byantigen-presenting cells and drives cell-mediated immunity by binding toa two-chain receptor complex that is expressed on the surface of T cellsor natural killer (NK) cells. The IL-12 receptor beta-1 (IL-12β1) chainbinds to the p40 subunit of IL-12, providing the primary interactionbetween IL-12 and its receptor. However, it is IL-12p35 ligation of thesecond receptor chain, IL-12β2, that confers intracellular signaling(e.g. STAT4 phosphorylation) and activation of the receptor-bearing cell(Presky et al, 1996). IL-12 signaling concurrent with antigenpresentation is thought to invoke T cell differentiation towards the Thelper 1 (Th1) phenotype, characterized by interferon gamma (IFNγ)production (Trinchieri, 2003). Th1 cells are believed to promoteimmunity to some intracellular pathogens, generate complement-fixingantibody isotypes, and contribute to tumor immunosurveillance. Thus,IL-12 is thought to be a significant component to host defense immunemechanisms.

It was discovered that the p40 protein subunit of IL-12 can alsoassociate with a separate protein subunit, designated p19, to form anovel cytokine, IL-23 (Oppman et al, 2000). IL-23 also signals through atwo-chain receptor complex. Since the p40 subunit is shared betweenIL-12 and IL-23, it follows that the IL-12β1 chain is also sharedbetween IL-12 and IL-23. However, it is the IL-23p19 ligation of thesecond component of the IL-23 receptor complex, IL-23R, that confersIL-23 specific intracellular signaling (e.g., STAT3 phosphorylation) andsubsequent IL-17 production by T cells (Parham et al, 2002; Aggarwal etal. 2003). Recent studies have demonstrated that the biologicalfunctions of IL-23 are distinct from those of IL-12, despite thestructural similarity between the two cytokines (Langrish et al, 2005).

Abnormal regulation of IL-12 and Th1 cell populations has beenassociated with many immune-mediated diseases since neutralization ofIL-12 by antibodies is effective in treating animal models of psoriasis,multiple sclerosis (MS), rheumatoid arthritis, inflammatory boweldisease, insulin-dependent (type 1) diabetes mellitus, and uveitis(Leonard et al, 1995; Hong et al, 1999; Malfait et al, 1998; Davidson etal, 1998). However, since these studies targeted the shared p40 subunit,both IL-12 and IL-23 were neutralized in vivo. Therefore, it was unclearwhether IL-12 or IL-23 was mediating disease, or if both cytokinesneeded to be inhibited to achieve disease suppression. Recent studieshave confirmed through IL-23p19 deficient mice or specific antibodyneutralization of IL-23 that IL-23 inhibition can provide equivalentbenefit as anti-IL-12p40 strategies (Cua et al, 2003, Murphy et al,2003, Benson et al 2004). Therefore, there is increasing evidence forthe specific role of IL-23 in immune-mediated disease. Neutralization ofIL-23 without inhibition of IL-12 pathways could then provide effectivetherapy of immune-mediated disease with limited impact on important hostdefense immune mechanism. This would represent a significant improvementover current therapeutic options.

Psoriasis is a common, chronic immune-mediated skin disorder withsignificant co-morbidities, such as psoriatic arthritis (PsA),depression, cardiovascular disease, hypertension, obesity, diabetes,metabolic syndrome, and Crohn's disease. Plaque psoriasis is the mostcommon form of the disease and manifests in well demarcated erythematouslesions topped with white silver scales. Plaques are pruritic, painful,often disfiguring and disabling, and a significant proportion ofpsoriatic patients have plaques on hands/nails face, feet and genitalia.As such, psoriasis negatively impacts health-related quality of life(HRQoL) to a significant extent, including imposing physical andpsychosocial burdens that extend beyond the physical dermatologicalsymptoms and interfere with everyday activities. For example, psoriasisnegatively impacts familial, spousal, social, and work relationships,and is associated with a higher incidence of depression and increasedsuicidal tendencies.

Histologic characterization of psoriasis lesions reveals a thickenedepidermis resulting from aberrant keratinocyte proliferation anddifferentiation as well as dermal infiltration and co-localization ofCD3+T lymphocytes and dendritic cells. While the etiology of psoriasisis not well defined, gene and protein analysis have shown that IL-12,IL-23 and their downstream molecules are over-expressed in psoriaticlesions, and some may correlate with psoriasis disease severity. Sometherapies used in the treatment of psoriasis modulate IL-12 and IL-23levels, which is speculated to contribute to their efficacy. Th1 andTh17 cells can produce effector cytokines that induce the production ofvasodilators, chemoattractants and expression of adhesion molecules onendothelial cells which in turn, promote monocyte and neutrophilrecruitment, T cell infiltration, neovascularization and keratinocyteactivation and hyperplasia. Activated keratinocytes can producechemoattractant factors that promote neutrophil, monocyte, T cell, anddendritic cell trafficking, thus establishing a cycle of inflammationand keratinocyte hyperproliferation.

Elucidation of the pathogenesis of psoriasis has led to effectivebiologic treatments targeting tumor necrosis factor-alpha (TNF-α), bothinterleukin (IL)-12 and IL-23 and, most recently, IL-17 as well as IL-23alone (including in Phase 1 and 2 clinical trials using guselkumab).Guselkumab (also known as CNTO 1959) is a fully human IgG1 lambdamonoclonal antibody that binds to the p19 subunit of IL-23 and inhibitsthe intracellular and downstream signaling of IL-23, required forterminal differentiation of T helper (Th)17 cells.

SUMMARY OF THE INVENTION

In a first aspect, the invention concerns a method of treating psoriasisin a patient comprising subcutaneously administering an anti-IL-23specific antibody (also referred to as IL-23p19 antibody), e.g.,guselkumab, to the patient, wherein the anti-IL-23 specific antibody isadministered at an initial dose, a dose 4 weeks thereafter, and at adosing interval of once every 8 weeks thereafter, e.g., a dose at 0, 4,8, 16, 24, 32, 40 and 48 weeks.

In the method of treating psoriasis in a patient, the patient treatedwith the antibody to IL-23 demonstrates greater efficacy in a psoriasisclinical endpoint than efficacy in the psoriasis clinical endpointachieved by a patient treated with the antibody secukinumab (marketed asCosentyx® by Novartis). The psoriasis clinical endpoint may be PASI90,PASI100, IGA 0 and/or IGA 1 and is measured 24, 28, 32, 36, 40, 44and/or 48 weeks after initial treatment, preferably, 48 weeks afterinitial treatment.

In the method of the invention, the antibody to IL-23 is administered inan initial dose, 4 weeks after the initial dose and every 8 weeks afterthe dose at 4 weeks and the secukinumab antibody is administered in aninitial dose, 1 week after the initial dose, 2 weeks after the initialdose, 3 weeks after the initial dose, 4 weeks after the initial dose andevery 4 weeks after the dose at 4 weeks. In an embodiment of the method,the antibody to IL-23 is administered at a dose of 100 mg and theantibody to IL-23 is safe and effective treating psoriasis at an area ofa patient selected from the group consisting of scalp, nails, hands andfeet.

In another embodiment of the method, the antibody to IL-23 is effectiveto reduce a symptom of psoriasis in the patient, induce clinicalresponse, induce or maintain clinical remission, inhibit diseaseprogression, or inhibit a disease complication in the patient and thepatient is treated for moderate to severe psoriasis.

In a further embodiment of the invention, the method further comprisesthe step of discontinuing treatment of a patient previously treated withat least one dose of secukinumab and deciding to treat the patient withguselkumab. In an additional embodiment, the method further comprisesthe step of measuring the psoriasis clinical endpoint PASI90, PASI100,IGA 0 and/or IGA 1 at 24, 28, 32, 36, 40, 44 and/or 48 weeks afterinitial treatment and discontinuing treatment of a patient previouslytreated with at least one dose of secukinumab and treating the patientwith guselkumab.

In another aspect, the composition used in the method of the inventioncomprises a pharmaceutical composition comprising: an anti-IL-23specific antibody in an amount from about 1.0 μg/ml to about 1000 mg/ml,specifically at 50 mg or 100 mg. In a preferred embodiment theanti-IL-23 specific antibody is guselkumab at 100 mg/mL; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.

In an embodiment, the psoriasis patient achieved the endpoints ofachieving an IGA score of cleared or minimal disease (IGA 0/1) and 90%improvement in PASI response (PASI 90) or 100% improvement in PASIresponse (PASI 100) at week 16.

In another aspect of the invention the pharmaceutical compositioncomprises an isolated anti-IL23 specific antibody having the guselkumabCDR sequences comprising (i) the heavy chain CDR amino acid sequences ofSEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 44; and (ii) the light chainCDR amino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO:73 at 100 mg/mL; 7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mML-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80of the pharmaceutical composition; wherein the diluent is water atstandard state.

Another aspect of the method of the invention comprises administering apharmaceutical composition comprising an isolated anti-IL-23 specificantibody having the guselkumab heavy chain variable region amino acidsequence of SEQ ID NO: 106 and the guselkumab light chain variableregion amino acid sequence of SEQ ID NO: 116 at 100 mg/mL; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A through FIG. 1D shows the proportions of subjects achieving aPASI 100 response (FIG. 1A), a PASI 90 response (FIG. 1B) an IGA scoreof cleared (0) (FIG. 1C), and an IGA score of cleared (0) or minimal (1)(FIG. 1D) from Week 1 through Week 48.

FIG. 2 is a diagram of the ECLIPSE study design.

FIG. 3 shows serum levels of IL-17F in psoriasis patients treated withguselkumab and secukinumab.

FIG. 4 shows serum levels of IL-22 in psoriasis patients treated withguselkumab and secukinumab.

FIG. 5 shows serum levels of BD-2 in psoriasis patients treated withguselkumab and secukinumab.

FIG. 6 shows the normalization of a subset of induced genes in psoriasislesional skin.

FIG. 7 shows the expression in psoriasis lesional skin of a group ofgenes associated with mucosal-associated invariant T (MAIT) cells

FIG. 8 shows the frequency of CD8 TRM in PSO skin treated withguselkumab and secukinumab.

FIG. 9 shows the frequency of regulatory T cells (Tregs) in PSO skintreated with guselkumab and secukinumab.

FIG. 10 shows the ratio of regulatory T cells (Tregs) to CD8 tissueresident memory T cells (TRMs) in PSO skin treated with guselkumab andsecukinumab.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the method of treatment of psoriasis comprisesadministering isolated, recombinant and/or synthetic anti-IL-23 specifichuman antibodies and diagnostic and therapeutic compositions, methodsand devices.

As used herein, an “anti-IL-23 specific antibody,” “anti-IL-23antibody,” “antibody portion,” or “antibody fragment” and/or “antibodyvariant” and the like include any protein or peptide containing moleculethat comprises at least a portion of an immunoglobulin molecule, such asbut not limited to, at least one complementarity determining region(CDR) of a heavy or light chain or a ligand binding portion thereof, aheavy chain or light chain variable region, a heavy chain or light chainconstant region, a framework region, or any portion thereof, or at leastone portion of an IL-23 receptor or binding protein, which can beincorporated into an antibody of the present invention. Such antibodyoptionally further affects a specific ligand, such as but not limitedto, where such antibody modulates, decreases, increases, antagonizes,agonizes, mitigates, alleviates, blocks, inhibits, abrogates and/orinterferes with at least one IL-23 activity or binding, or with IL-23receptor activity or binding, in vitro, in situ and/or in vivo. As anon-limiting example, a suitable anti-IL-23 antibody, specified portionor variant of the present invention can bind at least one IL-23molecule, or specified portions, variants or domains thereof. A suitableanti-IL-23 antibody, specified portion, or variant can also optionallyaffect at least one of IL-23 activity or function, such as but notlimited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptorsignaling, membrane IL-23 cleavage, IL-23 activity, IL-23 productionand/or synthesis.

The term “antibody” is further intended to encompass antibodies,digestion fragments, specified portions and variants thereof, includingantibody mimetics or comprising portions of antibodies that mimic thestructure and/or function of an antibody or specified fragment orportion thereof, including single chain antibodies and fragmentsthereof. Functional fragments include antigen-binding fragments thatbind to a mammalian IL-23. For example, antibody fragments capable ofbinding to IL-23 or portions thereof, including, but not limited to, Fab(e.g., by papain digestion), Fab′ (e.g., by pepsin digestion and partialreduction) and F(ab′)₂ (e.g., by pepsin digestion), facb (e.g., byplasmin digestion), pFc′ (e.g., by pepsin or plasmin digestion), Fd(e.g., by pepsin digestion, partial reduction and reaggregation), Fv orscFv (e.g., by molecular biology techniques) fragments, are encompassedby the invention (see, e.g., Colligan, Immunology, supra).

Such fragments can be produced by enzymatic cleavage, synthetic orrecombinant techniques, as known in the art and/or as described herein.Antibodies can also be produced in a variety of truncated forms usingantibody genes in which one or more stop codons have been introducedupstream of the natural stop site. For example, a combination geneencoding a F(ab′)₂ heavy chain portion can be designed to include DNAsequences encoding the C_(H)1 domain and/or hinge region of the heavychain. The various portions of antibodies can be joined togetherchemically by conventional techniques, or can be prepared as acontiguous protein using genetic engineering techniques.

As used herein, the term “human antibody” refers to an antibody in whichsubstantially every part of the protein (e.g., CDR, framework, C_(L),C_(H) domains (e.g., C_(H)1, C_(H)2, C_(H)3), hinge, (V_(L), V_(H))) issubstantially non-immunogenic in humans, with only minor sequencechanges or variations. A “human antibody” may also be an antibody thatis derived from or closely matches human germline immunoglobulinsequences. Human antibodies may include amino acid residues not encodedby germline immunoglobulin sequences (e.g., mutations introduced byrandom or site-specific mutagenesis in vitro or by somatic mutation invivo). Often, this means that the human antibody is substantiallynon-immunogenic in humans. Human antibodies have been classified intogroupings based on their amino acid sequence similarities. Accordingly,using a sequence similarity search, an antibody with a similar linearsequence can be chosen as a template to create a human antibody.Similarly, antibodies designated primate (monkey, baboon, chimpanzee,etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like)and other mammals designate such species, sub-genus, genus, sub-family,and family specific antibodies. Further, chimeric antibodies can includeany combination of the above. Such changes or variations optionally andpreferably retain or reduce the immunogenicity in humans or otherspecies relative to non-modified antibodies. Thus, a human antibody isdistinct from a chimeric or humanized antibody.

It is pointed out that a human antibody can be produced by a non-humananimal or prokaryotic or eukaryotic cell that is capable of expressingfunctionally rearranged human immunoglobulin (e.g., heavy chain and/orlight chain) genes. Further, when a human antibody is a single chainantibody, it can comprise a linker peptide that is not found in nativehuman antibodies. For example, an Fv can comprise a linker peptide, suchas two to about eight glycine or other amino acid residues, whichconnects the variable region of the heavy chain and the variable regionof the light chain. Such linker peptides are considered to be of humanorigin.

Bispecific, heterospecific, heteroconjugate or similar antibodies canalso be used that are monoclonal, preferably, human or humanized,antibodies that have binding specificities for at least two differentantigens. In the present case, one of the binding specificities is forat least one IL-23 protein, the other one is for any other antigen.Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy chain-light chainpairs, where the two heavy chains have different specificities (Milsteinand Cuello, Nature 305:537 (1983)). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of 10 different antibody molecules, of whichonly one has the correct bispecific structure. The purification of thecorrect molecule, which is usually done by affinity chromatographysteps, is rather cumbersome, and the product yields are low. Similarprocedures are disclosed, e.g., in WO 93/08829, U.S. Pat. Nos.6,210,668, 6,193,967, 6,132,992, 6,106,833, 6,060,285, 6,037,453,6,010,902, 5,989,530, 5,959,084, 5,959,083, 5,932,448, 5,833,985,5,821,333, 5,807,706, 5,643,759, 5,601,819, 5,582,996, 5,496,549,4,676,980, WO 91/00360, WO 92/00373, EP 03089, Traunecker et al., EMBOJ. 10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986),each entirely incorporated herein by reference.

Anti-IL-23 specific (also termed IL-23 specific antibodies) (orantibodies to IL-23) useful in the methods and compositions of thepresent invention can optionally be characterized by high affinitybinding to IL-23 and, optionally and preferably, having low toxicity. Inparticular, an antibody, specified fragment or variant of the invention,where the individual components, such as the variable region, constantregion and framework, individually and/or collectively, optionally andpreferably possess low immunogenicity, is useful in the presentinvention. The antibodies that can be used in the invention areoptionally characterized by their ability to treat patients for extendedperiods with measurable alleviation of symptoms and low and/oracceptable toxicity. Low or acceptable immunogenicity and/or highaffinity, as well as other suitable properties, can contribute to thetherapeutic results achieved. “Low immunogenicity” is defined herein asraising significant HAHA, HACA or HAMA responses in less than about 75%,or preferably less than about 50% of the patients treated and/or raisinglow titres in the patient treated (less than about 300, preferably lessthan about 100 measured with a double antigen enzyme immunoassay)(Elliott et al., Lancet 344:1125-1127 (1994), entirely incorporatedherein by reference). “Low immunogenicity” can also be defined as theincidence of titrable levels of antibodies to the anti-IL-23 antibody inpatients treated with anti-IL-23 antibody as occurring in less than 25%of patients treated, preferably, in less than 10% of patients treatedwith the recommended dose for the recommended course of therapy duringthe treatment period.

The terms “clinically proven efficacy” and “clinically proven effective”as used herein in the context of a dose, dosage regimen, treatment ormethod refer to the effectiveness of a particular dose, dosage ortreatment regimen. Efficacy can be measured based on change in thecourse of the disease in response to an agent of the present invention.For example, an anti-IL-23 antibody of the present invention (e.g., theanti-IL-23 antibody guselkumab) is administered to a patient in anamount and for a time sufficient to induce an improvement, preferably asustained improvement, in at least one indicator that reflects theseverity of the disorder that is being treated. Various indicators thatreflect the extent of the subject's illness, disease or condition may beassessed for determining whether the amount and time of the treatment issufficient. Such indicators include, for example, clinically recognizedindicators of disease severity, symptoms, or manifestations of thedisorder in question. The degree of improvement generally is determinedby a physician, who may make this determination based on signs,symptoms, biopsies, or other test results, and who may also employquestionnaires that are administered to the subject, such asquality-of-life questionnaires developed for a given disease. Forexample, an anti-IL23 antibody of the present invention may beadministered to achieve an improvement in a patient's condition relatedto psoriasis. Improvement may be indicated by an improvement in an indexof disease activity, by amelioration of clinical symptoms or by anyother measure of disease activity. Examples of such indices of diseaseare PASI75, PASI90, PASI100, IGA1 and IGA0. The Psoriasis Area andSeverity Index (PAST) is a score used by doctors and nurses to recordpsoriasis severity and PASI75 is shorthand for a 75% reduction of thePASI score from the start to the end of the trial (with PASI90 meaning a90% reduction and PASI100 meaning a 100% reduction). Investigator'sGlobal Assessment (IGA) tool is a visual assessment that consists of ascore ranging from 0 (clear) to 4 (severe). IGA0 signifies cleared andIGA1 signifies almost clear.

The term “clinically proven safe”, as it relates to a dose, dosageregimen, treatment or method with an anti-IL-23 antibody of the presentinvention (e.g., the anti-IL-23 antibody guselkumab), refers to afavorable risk:benefit ratio with an acceptable frequency and/oracceptable severity of treatment-emergent adverse events (referred to asAEs or TEAEs) compared to the standard of care or to another comparator.An adverse event is an untoward medical occurrence in a patientadministered a medicinal product. In particular, safe as it relates to adose, dosage regimen or treatment with an anti-IL-23 antibody of thepresent invention refers to with an acceptable frequency and/oracceptable severity of adverse events associated with administration ofthe antibody if attribution is considered to be possible, probable, orvery likely due to the use of the anti-IL23 antibody.

As used herein, unless otherwise noted, the term “clinically proven”(used independently or to modify the terms “safe” and/or “effective”)shall mean that it has been proven by a clinical trial wherein theclinical trial has met the approval standards of U.S. Food and DrugAdministration, EMEA or a corresponding national regulatory agency. Forexample, the clinical study may be an adequately sized, randomized,double-blinded study used to clinically prove the effects of the drug.

Utility

The isolated nucleic acids of the present invention can be used forproduction of at least one anti-IL-23 antibody or specified variantthereof, which can be used to measure or effect in an cell, tissue,organ or animal (including mammals and humans), to diagnose, monitor,modulate, treat, alleviate, help prevent the incidence of, or reduce thesymptoms of psoriasis.

Such a method can comprise administering an effective amount of acomposition or a pharmaceutical composition comprising at least oneanti-IL-23 antibody to a cell, tissue, organ, animal or patient in needof such modulation, treatment, alleviation, prevention, or reduction insymptoms, effects or mechanisms. The effective amount can comprise anamount of about 0.001 to 500 mg/kg per single (e.g., bolus), multiple orcontinuous administration, or to achieve a serum concentration of0.01-5000 μg/ml serum concentration per single, multiple, or continuousadministration, or any effective range or value therein, as done anddetermined using known methods, as described herein or known in therelevant arts.

Citations

All publications or patents cited herein, whether or not specificallydesignated, are entirely incorporated herein by reference as they showthe state of the art at the time of the present invention and/or toprovide description and enablement of the present invention.Publications refer to any scientific or patent publications, or anyother information available in any media format, including all recorded,electronic or printed formats. The following references are entirelyincorporated herein by reference: Ausubel, et al., ed., CurrentProtocols in Molecular Biology, John Wiley & Sons, Inc., NY, N.Y.(1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual,2^(nd) Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane,antibodies, a Laboratory Manual, Cold Spring Harbor, N.Y. (1989);Colligan, et al., eds., Current Protocols in Immunology, John Wiley &Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols inProtein Science, John Wiley & Sons, NY, N.Y., (1997-2001).

Antibodies of the Present Invention—Production and Generation

At least one anti-IL-23 antibody used in the method of the presentinvention can be optionally produced by a cell line, a mixed cell line,an immortalized cell or clonal population of immortalized cells, as wellknown in the art. See, e.g., Ausubel, et al., ed., Current Protocols inMolecular Biology, John Wiley & Sons, Inc., NY, N.Y. (1987-2001);Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2^(nd)Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane, antibodies, aLaboratory Manual, Cold Spring Harbor, N.Y. (1989); Colligan, et al.,eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001); Colligan et al., Current Protocols in Protein Science, JohnWiley & Sons, NY, N.Y., (1997-2001), each entirely incorporated hereinby reference.

A preferred anti-IL-23 antibody is guselkumab (also referred to asCNTO1959) having the heavy chain variable region amino acid sequence ofSEQ ID NO: 106 and the light chain variable region amino acid sequenceof SEQ ID NO: 116 and having the heavy chain CDR amino acid sequences ofSEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 44; and the light chain CDRamino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO: 73.Other anti-IL-23 antibodies have sequences listed herein and aredescribed in U.S. Pat. No. 7,935,344, the entire contents of which areincorporated herein by reference).

Human antibodies that are specific for human IL-23 proteins or fragmentsthereof can be raised against an appropriate immunogenic antigen, suchas an isolated IL-23 protein and/or a portion thereof (includingsynthetic molecules, such as synthetic peptides). Other specific orgeneral mammalian antibodies can be similarly raised. Preparation ofimmunogenic antigens, and monoclonal antibody production can beperformed using any suitable technique.

In one approach, a hybridoma is produced by fusing a suitable immortalcell line (e.g., a myeloma cell line, such as, but not limited to,Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1,JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO2A, or the like, or heteromylomas, fusion products thereof, or any cellor fusion cell derived therefrom, or any other suitable cell line asknown in the art) (see, e.g., www.atcc.org, www.lifetech.com., and thelike), with antibody producing cells, such as, but not limited to,isolated or cloned spleen, peripheral blood, lymph, tonsil, or otherimmune or B cell containing cells, or any other cells expressing heavyor light chain constant or variable or framework or CDR sequences,either as endogenous or heterologous nucleic acid, as recombinant orendogenous, viral, bacterial, algal, prokaryotic, amphibian, insect,reptilian, fish, mammalian, rodent, equine, ovine, goat, sheep, primate,eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA,chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triplestranded, hybridized, and the like or any combination thereof. See,e.g., Ausubel, supra, and Colligan, Immunology, supra, chapter 2,entirely incorporated herein by reference.

Antibody producing cells can also be obtained from the peripheral bloodor, preferably, the spleen or lymph nodes, of humans or other suitableanimals that have been immunized with the antigen of interest. Any othersuitable host cell can also be used for expressing heterologous orendogenous nucleic acid encoding an antibody, specified fragment orvariant thereof, of the present invention. The fused cells (hybridomas)or recombinant cells can be isolated using selective culture conditionsor other suitable known methods, and cloned by limiting dilution or cellsorting, or other known methods. Cells which produce antibodies with thedesired specificity can be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies of therequisite specificity can be used, including, but not limited to,methods that select recombinant antibody from a peptide or proteinlibrary (e.g., but not limited to, a bacteriophage, ribosome,oligonucleotide, RNA, cDNA, or the like, display library; e.g., asavailable from Cambridge antibody Technologies, Cambridgeshire, UK;MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK;Biolnvent, Lund, Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma,Berkeley, Calif.; Ixsys. See, e.g., EP 368,684, PCT/GB91/01134;PCT/GB92/01755; PCT/GB92/002240; PCT/GB92/00883; PCT/GB93/00605; U.S.Ser. No. 08/350,260 (May 12, 1994); PCT/GB94/01422; PCT/GB94/02662;PCT/GB97/01835; (CAT/MRC); WO90/14443; WO90/14424; WO90/14430;PCT/US94/1234; WO92/18619; WO96/07754; (Scripps); WO96/13583, WO97/08320(MorphoSys); WO95/16027 (Biolnvent); WO88/06630; WO90/3809 (Dyax); U.S.Pat. No. 4,704,692 (Enzon); PCT/US91/02989 (Affymax); WO89/06283; EP 371998; EP 550 400; (Xoma); EP 229 046; PCT/US91/07149 (Ixsys); orstochastically generated peptides or proteins—U.S. Pat. Nos. 5,723,323,5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, WO 86/05803, EP590 689 (Ixsys, predecessor of Applied Molecular Evolution (AME), eachentirely incorporated herein by reference)) or that rely uponimmunization of transgenic animals (e.g., SCID mice, Nguyen et al.,Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev.Biotechnol. 16:95-118 (1996); Eren et al., Immunol. 93:154-161 (1998),each entirely incorporated by reference as well as related patents andapplications) that are capable of producing a repertoire of humanantibodies, as known in the art and/or as described herein. Suchtechniques, include, but are not limited to, ribosome display (Hanes etal., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al.,Proc. Natl. Acad. Sci. USA, 95:14130-14135 (November 1998)); single cellantibody producing technologies (e.g., selected lymphocyte antibodymethod (“SLAM”) (U.S. Pat. No. 5,627,052, Wen et al., J. Immunol.17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA93:7843-7848 (1996)); gel microdroplet and flow cytometry (Powell etal., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, Mass.;Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al.,Bio/Technol. 13:787-790 (1995)); B-cell selection (Steenbakkers et al.,Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech,Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed.,Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)).

Methods for engineering or humanizing non-human or human antibodies canalso be used and are well known in the art. Generally, a humanized orengineered antibody has one or more amino acid residues from a sourcethat is non-human, e.g., but not limited to, mouse, rat, rabbit,non-human primate or other mammal. These non-human amino acid residuesare replaced by residues often referred to as “import” residues, whichare typically taken from an “import” variable, constant or other domainof a known human sequence.

Known human Ig sequences are disclosed, e.g.,www.ncbi.nlm.nih.gov/entrez/query.fcgi; www.ncbi.nih.gov/igblast;www.atcc.org/phage/hdb.html; www.mrc-cpe.cam.ac.uk/ALIGNMENTS.php;www.kabatdatabase.com/top.html; ftp.ncbi.nih.gov/repository/kabat;www.sciquest.com; www.abcam.com;www.antibodyresource.com/onlinecomp.html;www.public.iastate.edu/˜pedro/research_tools.html;www.whfreeman.com/immunology/CH05/kuby05.htm;www.hhmi.org/grants/lectures/1996/vlab;www.path.cam.ac.uk/˜mrc7/mikeimages.html;mcb.harvard.edu/BioLinks/Immunology.html; www.immunologylink.com;pathbox.wustl.edu/˜hcenter/index.html; www.appliedbiosystems.com;www.nal.usda.gov/awic/pubs/antibody;www.m.ehime-u.ac.jp/˜yasuhito/Elisa.html; www.biodesign.com;www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org;baserv.uci.kun.nl/˜jraats/links1.html;www.recab.uni-hd.de/immuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk;www.ibt.unam.mx/vir/V_mice.html; http://www.bioinforg.uk/abs;antibody.bath.ac.uk; www.unizh.ch; www.cryst.bbk.ac.uk/˜ubcg07s;www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.html;www.path.cam.ac.uk/˜mrc7/humanisation/TAHHP.html;www.ibt.unam.mx/vir/structure/stat_aim.html;www.biosci.missouri.edu/smithgp/index.html; www.jerini.de; Kabat et al.,Sequences of Proteins of Immunological Interest, U.S. Dept. Health(1983), each entirely incorporated herein by reference.

Such imported sequences can be used to reduce immunogenicity or reduce,enhance or modify binding, affinity, on-rate, off-rate, avidity,specificity, half-life, or any other suitable characteristic, as knownin the art. In general, the CDR residues are directly and mostsubstantially involved in influencing antigen binding. Accordingly, partor all of the non-human or human CDR sequences are maintained while thenon-human sequences of the variable and constant regions may be replacedwith human or other amino acids.

Antibodies can also optionally be humanized or human antibodiesengineered with retention of high affinity for the antigen and otherfavorable biological properties. To achieve this goal, humanized (orhuman) antibodies can be optionally prepared by a process of analysis ofthe parental sequences and various conceptual humanized products usingthree-dimensional models of the parental and humanized sequences.Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are availablewhich illustrate and display probable three-dimensional conformationalstructures of selected candidate immunoglobulin sequences. Inspection ofthese displays permits analysis of the likely role of the residues inthe functioning of the candidate immunoglobulin sequence, i.e., theanalysis of residues that influence the ability of the candidateimmunoglobulin to bind its antigen. In this way, framework (FR) residuescan be selected and combined from the consensus and import sequences sothat the desired antibody characteristic, such as increased affinity forthe target antigen(s), is achieved.

In addition, the human IL-23 specific antibody used in the method of thepresent invention may comprise a human germline light chain framework.In particular embodiments, the light chain germline sequence is selectedfrom human VK sequences including, but not limited to, A1, A10, A11,A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1,L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25,L4/18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and 08. Incertain embodiments, this light chain human germline framework isselected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20,V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15,V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3,V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6.

In other embodiments, the human IL-23 specific antibody used in themethod of the present invention may comprise a human germline heavychain framework. In particular embodiments, this heavy chain humangermline framework is selected from VH1-18, VH1-2, VH1-24, VH1-3,VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11,VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35,VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72,VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59,VH4-61, VH5-51, VH6-1, and VH7-81.

In particular embodiments, the light chain variable region and/or heavychain variable region comprises a framework region or at least a portionof a framework region (e.g., containing 2 or 3 subregions, such as FR2and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 isfully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 isfully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 isa germline sequence (e.g., human germline) or comprises human consensussequences for the particular framework (readily available at the sourcesof known human Ig sequences described above). In other embodiments, atleast FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., humangermline) or comprises human consensus sequences for the particularframework. In preferred embodiments, the framework region is a fullyhuman framework region.

Humanization or engineering of antibodies of the present invention canbe performed using any known method, such as but not limited to thosedescribed in, Winter (Jones et al., Nature 321:522 (1986); Riechmann etal., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)),Sims et al., J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Mol.Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A.89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), U.S. Pat.Nos. 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192,5,723,323, 5,766886, 5714352, 6204023, 6180370, 5693762, 5530101,5585089, 5225539; 4816567, PCT/US98/16280, US96/18978, US91/09630,US91/05939, US94/01234, GB89/01334, GB91/01134, GB92/01755; WO90/14443,WO90/14424, WO90/14430, EP 229246, each entirely incorporated herein byreference, included references cited therein.

In certain embodiments, the antibody comprises an altered (e.g.,mutated) Fc region. For example, in some embodiments, the Fc region hasbeen altered to reduce or enhance the effector functions of theantibody. In some embodiments, the Fc region is an isotype selected fromIgM, IgA, IgG, IgE, or other isotype. Alternatively or additionally, itmay be useful to combine amino acid modifications with one or morefurther amino acid modifications that alter C1q binding and/or thecomplement dependent cytotoxicity function of the Fc region of an IL-23binding molecule. The starting polypeptide of particular interest may beone that binds to C1q and displays complement dependent cytotoxicity(CDC). Polypeptides with pre-existing C1q binding activity, optionallyfurther having the ability to mediate CDC may be modified such that oneor both of these activities are enhanced. Amino acid modifications thatalter C1q and/or modify its complement dependent cytotoxicity functionare described, for example, in WO0042072, which is hereby incorporatedby reference.

As disclosed above, one can design an Fc region of the human IL-23specific antibody of the present invention with altered effectorfunction, e.g., by modifying C1q binding and/or FcγR binding and therebychanging complement dependent cytotoxicity (CDC) activity and/orantibody-dependent cell-mediated cytotoxicity (ADCC) activity. “Effectorfunctions” are responsible for activating or diminishing a biologicalactivity (e.g., in a subject). Examples of effector functions include,but are not limited to: C1q binding; CDC; Fc receptor binding; ADCC;phagocytosis; down regulation of cell surface receptors (e.g., B cellreceptor; BCR), etc. Such effector functions may require the Fc regionto be combined with a binding domain (e.g., an antibody variable domain)and can be assessed using various assays (e.g., Fc binding assays, ADCCassays, CDC assays, etc.).

For example, one can generate a variant Fc region of the human IL-23 (oranti-IL-23) antibody with improved C1q binding and improvedFcγRIIIbinding (e.g., having both improved ADCC activity and improvedCDC activity). Alternatively, if it is desired that effector function bereduced or ablated, a variant Fc region can be engineered with reducedCDC activity and/or reduced ADCC activity. In other embodiments, onlyone of these activities may be increased, and, optionally, also theother activity reduced (e.g., to generate an Fc region variant withimproved ADCC activity, but reduced CDC activity and vice versa).

Fc mutations can also be introduced in engineer to alter theirinteraction with the neonatal Fc receptor (FcRn) and improve theirpharmacokinetic properties. A collection of human Fc variants withimproved binding to the FcRn have been described (Shields et al.,(2001). High resolution mapping of the binding site on human IgG1 forFcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants withimproved binding to the FcγR, J. Biol. Chem. 276:6591-6604).

Another type of amino acid substitution serves to alter theglycosylation pattern of the Fc region of the human IL-23 specificantibody. Glycosylation of an Fc region is typically either N-linked orO-linked. N-linked refers to the attachment of the carbohydrate moietyto the side chain of an asparagine residue. O-linked glycosylationrefers to the attachment of one of the sugars N-aceylgalactosamine,galactose, or xylose to a hydroxyamino acid, most commonly serine orthreonine, although 5-hydroxyproline or 5-hydroxylysine may also beused. The recognition sequences for enzymatic attachment of thecarbohydrate moiety to the asparagine side chain peptide sequences areasparagine-X-serine and asparagine-X-threonine, where X is any aminoacid except proline. Thus, the presence of either of these peptidesequences in a polypeptide creates a potential glycosylation site.

The glycosylation pattern may be altered, for example, by deleting oneor more glycosylation site(s) found in the polypeptide, and/or addingone or more glycosylation sites that are not present in the polypeptide.Addition of glycosylation sites to the Fc region of a human IL-23specific antibody is conveniently accomplished by altering the aminoacid sequence such that it contains one or more of the above-describedtripeptide sequences (for N-linked glycosylation sites). An exemplaryglycosylation variant has an amino acid substitution of residue Asn 297of the heavy chain. The alteration may also be made by the addition of,or substitution by, one or more serine or threonine residues to thesequence of the original polypeptide (for O-linked glycosylation sites).Additionally, a change of Asn 297 to Ala can remove one of theglycosylation sites.

In certain embodiments, the human IL-23 specific antibody of the presentinvention is expressed in cells that express beta(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT IIIadds GlcNAc to the human IL-23 antibody. Methods for producingantibodies in such a fashion are provided in WO/9954342, WO/03011878,patent publication 20030003097A1, and Umana et al., NatureBiotechnology, 17:176-180, February 1999; all of which are hereinspecifically incorporated by reference in their entireties.

The anti-IL-23 antibody can also be optionally generated by immunizationof a transgenic animal (e.g., mouse, rat, hamster, non-human primate,and the like) capable of producing a repertoire of human antibodies, asdescribed herein and/or as known in the art. Cells that produce a humananti-IL-23 antibody can be isolated from such animals and immortalizedusing suitable methods, such as the methods described herein.

Transgenic mice that can produce a repertoire of human antibodies thatbind to human antigens can be produced by known methods (e.g., but notlimited to, U.S. Pat. Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126,5,625,825, 5,633,425, 5,661,016 and 5,789,650 issued to Lonberg et al.;Jakobovits et al. WO 98/50433, Jakobovits et al. WO 98/24893, Lonberg etal. WO 98/24884, Lonberg et al. WO 97/13852, Lonberg et al. WO 94/25585,Kucherlapate et al. WO 96/34096, Kucherlapate et al. EP 0463 151 B1,Kucherlapate et al. EP 0710 719 A1, Surani et al. U.S. Pat. No.5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al. EP 0438 474B1, Lonberg et al. EP 0814 259 A2, Lonberg et al. GB 2 272 440 A,Lonberg et al. Nature 368:856-859 (1994), Taylor et al., Int. Immunol.6(4)579-591 (1994), Green et al, Nature Genetics 7:13-21 (1994), Mendezet al., Nature Genetics 15:146-156 (1997), Taylor et al., Nucleic AcidsResearch 20(23):6287-6295 (1992), Tuaillon et al., Proc Natl Acad SciUSA 90(8)3720-3724 (1993), Lonberg et al., Int Rev Immunol 13(1):65-93(1995) and Fishwald et al., Nat Biotechnol 14(7):845-851 (1996), whichare each entirely incorporated herein by reference). Generally, thesemice comprise at least one transgene comprising DNA from at least onehuman immunoglobulin locus that is functionally rearranged, or which canundergo functional rearrangement. The endogenous immunoglobulin loci insuch mice can be disrupted or deleted to eliminate the capacity of theanimal to produce antibodies encoded by endogenous genes.

Screening antibodies for specific binding to similar proteins orfragments can be conveniently achieved using peptide display libraries.This method involves the screening of large collections of peptides forindividual members having the desired function or structure. Antibodyscreening of peptide display libraries is well known in the art. Thedisplayed peptide sequences can be from 3 to 5000 or more amino acids inlength, frequently from 5-100 amino acids long, and often from about 8to 25 amino acids long. In addition to direct chemical synthetic methodsfor generating peptide libraries, several recombinant DNA methods havebeen described. One type involves the display of a peptide sequence onthe surface of a bacteriophage or cell. Each bacteriophage or cellcontains the nucleotide sequence encoding the particular displayedpeptide sequence. Such methods are described in PCT Patent PublicationNos. 91/17271, 91/18980, 91/19818, and 93/08278.

Other systems for generating libraries of peptides have aspects of bothin vitro chemical synthesis and recombinant methods. See, PCT PatentPublication Nos. 92/05258, 92/14843, and 96/19256. See also, U.S. Pat.Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, andscreening kits are commercially available from such suppliers asInvitrogen (Carlsbad, Calif.), and Cambridge antibody Technologies(Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4,704,692, 4,939,666,4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730,5,763,733, 5,767,260, 5,856,456, assigned to Enzon; U.S. Pat. Nos.5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax, 5427908,5580717, assigned to Affymax; 5885793, assigned to Cambridge antibodyTechnologies; 5750373, assigned to Genentech, 5618920, 5595898, 5576195,5698435, 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel,supra; or Sambrook, supra, each of the above patents and publicationsentirely incorporated herein by reference.

Antibodies used in the method of the present invention can also beprepared using at least one anti-IL23 antibody encoding nucleic acid toprovide transgenic animals or mammals, such as goats, cows, horses,sheep, rabbits, and the like, that produce such antibodies in theirmilk. Such animals can be provided using known methods. See, e.g., butnot limited to, U.S. Pat. Nos. 5,827,690; 5,849,992; 4,873,316;5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of whichis entirely incorporated herein by reference.

Antibodies used in the method of the present invention can additionallybe prepared using at least one anti-IL23 antibody encoding nucleic acidto provide transgenic plants and cultured plant cells (e.g., but notlimited to, tobacco and maize) that produce such antibodies, specifiedportions or variants in the plant parts or in cells cultured therefrom.As a non-limiting example, transgenic tobacco leaves expressingrecombinant proteins have been successfully used to provide largeamounts of recombinant proteins, e.g., using an inducible promoter. See,e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) andreferences cited therein. Also, transgenic maize have been used toexpress mammalian proteins at commercial production levels, withbiological activities equivalent to those produced in other recombinantsystems or purified from natural sources. See, e.g., Hood et al., Adv.Exp. Med. Biol. 464:127-147 (1999) and references cited therein.Antibodies have also been produced in large amounts from transgenicplant seeds including antibody fragments, such as single chainantibodies (scFv's), including tobacco seeds and potato tubers. See,e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and referencescited therein. Thus, antibodies of the present invention can also beproduced using transgenic plants, according to known methods. See also,e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (October,1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., PlantPhysiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans.22:940-944 (1994); and references cited therein. Each of the abovereferences is entirely incorporated herein by reference.

The antibodies used in the method of the invention can bind human IL-23with a wide range of affinities (K_(D)). In a preferred embodiment, ahuman mAb can optionally bind human IL-23 with high affinity. Forexample, a human mAb can bind human IL-23 with a K_(D) equal to or lessthan about 10⁻⁷M, such as but not limited to, 0.1-9.9 (or any range orvalue therein)×10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³ or any rangeor value therein.

The affinity or avidity of an antibody for an antigen can be determinedexperimentally using any suitable method. (See, for example, Berzofsky,et al., “Antibody-Antigen Interactions,” In Fundamental Immunology,Paul, W. E., Ed., Raven Press: New York, N.Y. (1984); Kuby, JanisImmunology, W. H. Freeman and Company: New York, N.Y. (1992); andmethods described herein). The measured affinity of a particularantibody-antigen interaction can vary if measured under differentconditions (e.g., salt concentration, pH). Thus, measurements ofaffinity and other antigen-binding parameters (e.g., K_(D), K_(a),K_(d)) are preferably made with standardized solutions of antibody andantigen, and a standardized buffer, such as the buffer described herein.

Nucleic Acid Molecules

Using the information provided herein, for example, the nucleotidesequences encoding at least 70-100% of the contiguous amino acids of atleast one of the light or heavy chain variable or CDR regions describedherein, among other sequences disclosed herein, specified fragments,variants or consensus sequences thereof, or a deposited vectorcomprising at least one of these sequences, a nucleic acid molecule ofthe present invention encoding at least one anti-IL-23 antibody can beobtained using methods described herein or as known in the art.

Nucleic acid molecules of the present invention can be in the form ofRNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA,including, but not limited to, cDNA and genomic DNA obtained by cloningor produced synthetically, or any combinations thereof. The DNA can betriple-stranded, double-stranded or single-stranded, or any combinationthereof. Any portion of at least one strand of the DNA or RNA can be thecoding strand, also known as the sense strand, or it can be thenon-coding strand, also referred to as the anti-sense strand.

Isolated nucleic acid molecules used in the method of the presentinvention can include nucleic acid molecules comprising an open readingframe (ORF), optionally, with one or more introns, e.g., but not limitedto, at least one specified portion of at least one CDR, such as CDR1,CDR2 and/or CDR3 of at least one heavy chain or light chain; nucleicacid molecules comprising the coding sequence for an anti-IL-23 antibodyor variable region; and nucleic acid molecules which comprise anucleotide sequence substantially different from those described abovebut which, due to the degeneracy of the genetic code, still encode atleast one anti-IL-23 antibody as described herein and/or as known in theart. Of course, the genetic code is well known in the art. Thus, itwould be routine for one skilled in the art to generate such degeneratenucleic acid variants that code for specific anti-IL-23 antibodies usedin the method of the present invention. See, e.g., Ausubel, et al.,supra, and such nucleic acid variants are included in the presentinvention. Non-limiting examples of isolated nucleic acid moleculesinclude nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LCCDR2, and LC CDR3, respectively.

As indicated herein, nucleic acid molecules which comprise a nucleicacid encoding an anti-IL-23 antibody can include, but are not limitedto, those encoding the amino acid sequence of an antibody fragment, byitself; the coding sequence for the entire antibody or a portionthereof; the coding sequence for an antibody, fragment or portion, aswell as additional sequences, such as the coding sequence of at leastone signal leader or fusion peptide, with or without the aforementionedadditional coding sequences, such as at least one intron, together withadditional, non-coding sequences, including but not limited to,non-coding 5′ and 3′ sequences, such as the transcribed, non-translatedsequences that play a role in transcription, mRNA processing, includingsplicing and polyadenylation signals (for example, ribosome binding andstability of mRNA); an additional coding sequence that codes foradditional amino acids, such as those that provide additionalfunctionalities. Thus, the sequence encoding an antibody can be fused toa marker sequence, such as a sequence encoding a peptide thatfacilitates purification of the fused antibody comprising an antibodyfragment or portion.

Polynucleotides Selectively Hybridizing to a Polynucleotide as DescribedHerein

The method of the present invention uses isolated nucleic acids thathybridize under selective hybridization conditions to a polynucleotidedisclosed herein. Thus, the polynucleotides of this embodiment can beused for isolating, detecting, and/or quantifying nucleic acidscomprising such polynucleotides. For example, polynucleotides of thepresent invention can be used to identify, isolate, or amplify partialor full-length clones in a deposited library. In some embodiments, thepolynucleotides are genomic or cDNA sequences isolated, or otherwisecomplementary to, a cDNA from a human or mammalian nucleic acid library.

Preferably, the cDNA library comprises at least 80% full-lengthsequences, preferably, at least 85% or 90% full-length sequences, and,more preferably, at least 95% full-length sequences. The cDNA librariescan be normalized to increase the representation of rare sequences. Lowor moderate stringency hybridization conditions are typically, but notexclusively, employed with sequences having a reduced sequence identityrelative to complementary sequences. Moderate and high stringencyconditions can optionally be employed for sequences of greater identity.Low stringency conditions allow selective hybridization of sequenceshaving about 70% sequence identity and can be employed to identifyorthologous or paralogous sequences.

Optionally, polynucleotides will encode at least a portion of anantibody. The polynucleotides embrace nucleic acid sequences that can beemployed for selective hybridization to a polynucleotide encoding anantibody of the present invention. See, e.g., Ausubel, supra; Colligan,supra, each entirely incorporated herein by reference.

Construction of Nucleic Acids

The isolated nucleic acids can be made using (a) recombinant methods,(b) synthetic techniques, (c) purification techniques, and/or (d)combinations thereof, as well-known in the art.

The nucleic acids can conveniently comprise sequences in addition to apolynucleotide of the present invention. For example, a multi-cloningsite comprising one or more endonuclease restriction sites can beinserted into the nucleic acid to aid in isolation of thepolynucleotide. Also, translatable sequences can be inserted to aid inthe isolation of the translated polynucleotide of the present invention.For example, a hexa-histidine marker sequence provides a convenientmeans to purify the proteins of the present invention. The nucleic acidof the present invention, excluding the coding sequence, is optionally avector, adapter, or linker for cloning and/or expression of apolynucleotide of the present invention.

Additional sequences can be added to such cloning and/or expressionsequences to optimize their function in cloning and/or expression, toaid in isolation of the polynucleotide, or to improve the introductionof the polynucleotide into a cell. Use of cloning vectors, expressionvectors, adapters, and linkers is well known in the art. (See, e.g.,Ausubel, supra; or Sambrook, supra)

Recombinant Methods for Constructing Nucleic Acids

The isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA,or any combination thereof, can be obtained from biological sourcesusing any number of cloning methodologies known to those of skill in theart. In some embodiments, oligonucleotide probes that selectivelyhybridize, under stringent conditions, to the polynucleotides of thepresent invention are used to identify the desired sequence in a cDNA orgenomic DNA library. The isolation of RNA, and construction of cDNA andgenomic libraries, are well known to those of ordinary skill in the art.(See, e.g., Ausubel, supra; or Sambrook, supra)

Nucleic Acid Screening and Isolation Methods

A cDNA or genomic library can be screened using a probe based upon thesequence of a polynucleotide used in the method of the presentinvention, such as those disclosed herein. Probes can be used tohybridize with genomic DNA or cDNA sequences to isolate homologous genesin the same or different organisms. Those of skill in the art willappreciate that various degrees of stringency of hybridization can beemployed in the assay; and either the hybridization or the wash mediumcan be stringent. As the conditions for hybridization become morestringent, there must be a greater degree of complementarity between theprobe and the target for duplex formation to occur. The degree ofstringency can be controlled by one or more of temperature, ionicstrength, pH and the presence of a partially denaturing solvent, such asformamide. For example, the stringency of hybridization is convenientlyvaried by changing the polarity of the reactant solution through, forexample, manipulation of the concentration of formamide within the rangeof 0% to 50%. The degree of complementarity (sequence identity) requiredfor detectable binding will vary in accordance with the stringency ofthe hybridization medium and/or wash medium. The degree ofcomplementarity will optimally be 100%, or 70-100%, or any range orvalue therein. However, it should be understood that minor sequencevariations in the probes and primers can be compensated for by reducingthe stringency of the hybridization and/or wash medium.

Methods of amplification of RNA or DNA are well known in the art and canbe used according to the present invention without undueexperimentation, based on the teaching and guidance presented herein.

Known methods of DNA or RNA amplification include, but are not limitedto, polymerase chain reaction (PCR) and related amplification processes(see, e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188,to Mullis, et al.; 4,795,699 and 4,921,794 to Tabor, et al; U.S. Pat.No. 5,142,033 to Innis; U.S. Pat. No. 5,122,464 to Wilson, et al.; U.S.Pat. No. 5,091,310 to Innis; U.S. Pat. No. 5,066,584 to Gyllensten, etal; U.S. Pat. No. 4,889,818 to Gelfand, et al; U.S. Pat. No. 4,994,370to Silver, et al; U.S. Pat. No. 4,766,067 to Biswas; U.S. Pat. No.4,656,134 to Ringold) and RNA mediated amplification that usesanti-sense RNA to the target sequence as a template for double-strandedDNA synthesis (U.S. Pat. No. 5,130,238 to Malek, et al, with thetradename NASBA), the entire contents of which references areincorporated herein by reference. (See, e.g., Ausubel, supra; orSambrook, supra.)

For instance, polymerase chain reaction (PCR) technology can be used toamplify the sequences of polynucleotides used in the method of thepresent invention and related genes directly from genomic DNA or cDNAlibraries. PCR and other in vitro amplification methods can also beuseful, for example, to clone nucleic acid sequences that code forproteins to be expressed, to make nucleic acids to use as probes fordetecting the presence of the desired mRNA in samples, for nucleic acidsequencing, or for other purposes. Examples of techniques sufficient todirect persons of skill through in vitro amplification methods are foundin Berger, supra, Sambrook, supra, and Ausubel, supra, as well asMullis, et al., U.S. Pat. No. 4,683,202 (1987); and Innis, et al., PCRProtocols A Guide to Methods and Applications, Eds., Academic PressInc., San Diego, Calif. (1990). Commercially available kits for genomicPCR amplification are known in the art. See, e.g., Advantage-GC GenomicPCR Kit (Clontech). Additionally, e.g., the T4 gene 32 protein(Boehringer Mannheim) can be used to improve yield of long PCR products.

Synthetic Methods for Constructing Nucleic Acids

The isolated nucleic acids used in the method of the present inventioncan also be prepared by direct chemical synthesis by known methods (see,e.g., Ausubel, et al., supra). Chemical synthesis generally produces asingle-stranded oligonucleotide, which can be converted intodouble-stranded DNA by hybridization with a complementary sequence, orby polymerization with a DNA polymerase using the single strand as atemplate. One of skill in the art will recognize that while chemicalsynthesis of DNA can be limited to sequences of about 100 or more bases,longer sequences can be obtained by the ligation of shorter sequences.

Recombinant Expression Cassettes

The present invention uses recombinant expression cassettes comprising anucleic acid. A nucleic acid sequence, for example, a cDNA or a genomicsequence encoding an antibody used in the method of the presentinvention, can be used to construct a recombinant expression cassettethat can be introduced into at least one desired host cell. Arecombinant expression cassette will typically comprise a polynucleotideoperably linked to transcriptional initiation regulatory sequences thatwill direct the transcription of the polynucleotide in the intended hostcell. Both heterologous and non-heterologous (i.e., endogenous)promoters can be employed to direct expression of the nucleic acids.

In some embodiments, isolated nucleic acids that serve as promoter,enhancer, or other elements can be introduced in the appropriateposition (upstream, downstream or in the intron) of a non-heterologousform of a polynucleotide of the present invention so as to up or downregulate expression of a polynucleotide. For example, endogenouspromoters can be altered in vivo or in vitro by mutation, deletionand/or substitution.

Vectors and Host Cells

The present invention also relates to vectors that include isolatednucleic acid molecules, host cells that are genetically engineered withthe recombinant vectors, and the production of at least one anti-IL-23antibody by recombinant techniques, as is well known in the art. See,e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirelyincorporated herein by reference.

The polynucleotides can optionally be joined to a vector containing aselectable marker for propagation in a host. Generally, a plasmid vectoris introduced in a precipitate, such as a calcium phosphate precipitate,or in a complex with a charged lipid. If the vector is a virus, it canbe packaged in vitro using an appropriate packaging cell line and thentransduced into host cells.

The DNA insert should be operatively linked to an appropriate promoter.The expression constructs will further contain sites for transcriptioninitiation, termination and, in the transcribed region, a ribosomebinding site for translation. The coding portion of the maturetranscripts expressed by the constructs will preferably include atranslation initiating at the beginning and a termination codon (e.g.,UAA, UGA or UAG) appropriately positioned at the end of the mRNA to betranslated, with UAA and UAG preferred for mammalian or eukaryotic cellexpression.

Expression vectors will preferably but optionally include at least oneselectable marker. Such markers include, e.g., but are not limited to,methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. Nos.4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017,ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase(GS, U.S. Pat. Nos. 5,122,464; 5,770,359; 5,827,739) resistance foreukaryotic cell culture, and tetracycline or ampicillin resistance genesfor culturing in E. coli and other bacteria or prokaryotics (the abovepatents are entirely incorporated hereby by reference). Appropriateculture mediums and conditions for the above-described host cells areknown in the art. Suitable vectors will be readily apparent to theskilled artisan. Introduction of a vector construct into a host cell canbe effected by calcium phosphate transfection, DEAE-dextran mediatedtransfection, cationic lipid-mediated transfection, electroporation,transduction, infection or other known methods. Such methods aredescribed in the art, such as Sambrook, supra, Chapters 1-4 and 16-18;Ausubel, supra, Chapters 1, 9, 13, 15, 16.

At least one antibody used in the method of the present invention can beexpressed in a modified form, such as a fusion protein, and can includenot only secretion signals, but also additional heterologous functionalregions. For instance, a region of additional amino acids, particularlycharged amino acids, can be added to the N-terminus of an antibody toimprove stability and persistence in the host cell, during purification,or during subsequent handling and storage. Also, peptide moieties can beadded to an antibody of the present invention to facilitatepurification. Such regions can be removed prior to final preparation ofan antibody or at least one fragment thereof. Such methods are describedin many standard laboratory manuals, such as Sambrook, supra, Chapters17.29-17.42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18.

Those of ordinary skill in the art are knowledgeable in the numerousexpression systems available for expression of a nucleic acid encoding aprotein used in the method of the present invention. Alternatively,nucleic acids can be expressed in a host cell by turning on (bymanipulation) in a host cell that contains endogenous DNA encoding anantibody. Such methods are well known in the art, e.g., as described inU.S. Pat. Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, entirelyincorporated herein by reference.

Illustrative of cell cultures useful for the production of theantibodies, specified portions or variants thereof, are mammalian cells.Mammalian cell systems often will be in the form of monolayers of cellsalthough mammalian cell suspensions or bioreactors can also be used. Anumber of suitable host cell lines capable of expressing intactglycosylated proteins have been developed in the art, and include theCOS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21(e.g., ATCC CRL-10), CHO (e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCCCRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653,SP2/0-Ag14, 293 cells, HeLa cells and the like, which are readilyavailable from, for example, American Type Culture Collection, Manassas,Va. (www.atcc.org). Preferred host cells include cells of lymphoidorigin, such as myeloma and lymphoma cells. Particularly preferred hostcells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) andSP2/0-Ag14 cells (ATCC Accession Number CRL-1851). In a particularlypreferred embodiment, the recombinant cell is a P3X63Ab8.653 or aSP2/0-Ag14 cell.

Expression vectors for these cells can include one or more of thefollowing expression control sequences, such as, but not limited to, anorigin of replication; a promoter (e.g., late or early SV40 promoters,the CMV promoter (U.S. Pat. Nos. 5,168,062; 5,385,839), an HSV tkpromoter, a pgk (phosphoglycerate kinase) promoter, an EF-1 alphapromoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulinpromoter; an enhancer, and/or processing information sites, such asribosome binding sites, RNA splice sites, polyadenylation sites (e.g.,an SV40 large T Ag poly A addition site), and transcriptional terminatorsequences. See, e.g., Ausubel et al., supra; Sambrook, et al., supra.Other cells useful for production of nucleic acids or proteins of thepresent invention are known and/or available, for instance, from theAmerican Type Culture Collection Catalogue of Cell Lines and Hybridomas(www.atcc.org) or other known or commercial sources.

When eukaryotic host cells are employed, polyadenlyation ortranscription terminator sequences are typically incorporated into thevector. An example of a terminator sequence is the polyadenlyationsequence from the bovine growth hormone gene. Sequences for accuratesplicing of the transcript can also be included. An example of asplicing sequence is the VP1 intron from SV40 (Sprague, et al., J.Virol. 45:773-781 (1983)). Additionally, gene sequences to controlreplication in the host cell can be incorporated into the vector, asknown in the art.

Purification of an Antibody

An anti-IL-23 antibody can be recovered and purified from recombinantcell cultures by well-known methods including, but not limited to,protein A purification, ammonium sulfate or ethanol precipitation, acidextraction, anion or cation exchange chromatography, phosphocellulosechromatography, hydrophobic interaction chromatography, affinitychromatography, hydroxylapatite chromatography and lectinchromatography. High performance liquid chromatography (“HPLC”) can alsobe employed for purification. See, e.g., Colligan, Current Protocols inImmunology, or Current Protocols in Protein Science, John Wiley & Sons,NY, N.Y., (1997-2001), e.g., Chapters 1, 4, 6, 8, 9, 10, each entirelyincorporated herein by reference.

Antibodies used in the method of the present invention include naturallypurified products, products of chemical synthetic procedures, andproducts produced by recombinant techniques from a eukaryotic host,including, for example, yeast, higher plant, insect and mammalian cells.Depending upon the host employed in a recombinant production procedure,the antibody can be glycosylated or can be non-glycosylated, withglycosylated preferred. Such methods are described in many standardlaboratory manuals, such as Sambrook, supra, Sections 17.37-17.42;Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, Colligan, ProteinScience, supra, Chapters 12-14, all entirely incorporated herein byreference.

Anti-IL-23 Antibodies.

An anti-IL-23 antibody according to the present invention includes anyprotein or peptide containing molecule that comprises at least a portionof an immunoglobulin molecule, such as but not limited to, at least oneligand binding portion (LBP), such as but not limited to, acomplementarity determining region (CDR) of a heavy or light chain or aligand binding portion thereof, a heavy chain or light chain variableregion, a framework region (e.g., FR1, FR2, FR3, FR4 or fragmentthereof, further optionally comprising at least one substitution,insertion or deletion), a heavy chain or light chain constant region,(e.g., comprising at least one C_(H)1, hinge1, hinge2, hinge3, hinge4,C_(H)2, or C_(H)3 or fragment thereof, further optionally comprising atleast one substitution, insertion or deletion), or any portion thereof,that can be incorporated into an antibody. An antibody can include or bederived from any mammal, such as but not limited to, a human, a mouse, arabbit, a rat, a rodent, a primate, or any combination thereof, and thelike.

The isolated antibodies used in the method of the present inventioncomprise the antibody amino acid sequences disclosed herein encoded byany suitable polynucleotide, or any isolated or prepared antibody.Preferably, the human antibody or antigen-binding fragment binds humanIL-23 and, thereby, partially or substantially neutralizes at least onebiological activity of the protein. An antibody, or specified portion orvariant thereof, that partially or preferably substantially neutralizesat least one biological activity of at least one IL-23 protein orfragment can bind the protein or fragment and thereby inhibit activitiesmediated through the binding of IL-23 to the IL-23 receptor or throughother IL-23-dependent or mediated mechanisms. As used herein, the term“neutralizing antibody” refers to an antibody that can inhibit anIL-23-dependent activity by about 20-120%, preferably by at least about10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, 100% or more depending on the assay. The capacity of ananti-IL-23 antibody to inhibit an IL-23-dependent activity is preferablyassessed by at least one suitable IL-23 protein or receptor assay, asdescribed herein and/or as known in the art. A human antibody can be ofany class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise akappa or lambda light chain. In one embodiment, the human antibodycomprises an IgG heavy chain or defined fragment, for example, at leastone of isotypes, IgG1, IgG2, IgG3 or IgG4 (e.g., γ1, γ2, γ3, γ4).Antibodies of this type can be prepared by employing a transgenic mouseor other trangenic non-human mammal comprising at least one human lightchain (e.g., IgG, IgA, and IgM) transgenes as described herein and/or asknown in the art. In another embodiment, the anti-IL-23 human antibodycomprises an IgG1 heavy chain and an IgG1 light chain.

An antibody binds at least one specified epitope specific to at leastone IL-23 protein, subunit, fragment, portion or any combinationthereof. The at least one epitope can comprise at least one antibodybinding region that comprises at least one portion of the protein, whichepitope is preferably comprised of at least one extracellular, soluble,hydrophillic, external or cytoplasmic portion of the protein.

Generally, the human antibody or antigen-binding fragment will comprisean antigen-binding region that comprises at least one humancomplementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one heavy chain variable region and at least one humancomplementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one light chain variable region. The CDR sequences may bederived from human germline sequences or closely match the germlinesequences. For example, the CDRs from a synthetic library derived fromthe original non-human CDRs can be used. These CDRs may be formed byincorporation of conservative substitutions from the original non-humansequence. In another particular embodiment, the antibody orantigen-binding portion or variant can have an antigen-binding regionthat comprises at least a portion of at least one light chain CDR (i.e.,CDR1, CDR2 and/or CDR3) having the amino acid sequence of thecorresponding CDRs 1, 2 and/or 3.

Such antibodies can be prepared by chemically joining together thevarious portions (e.g., CDRs, framework) of the antibody usingconventional techniques, by preparing and expressing a (i.e., one ormore) nucleic acid molecule that encodes the antibody using conventionaltechniques of recombinant DNA technology or by using any other suitablemethod.

The anti-IL-23 specific antibody can comprise at least one of a heavy orlight chain variable region having a defined amino acid sequence. Forexample, in a preferred embodiment, the anti-IL-23 antibody comprises atleast one of at least one heavy chain variable region, optionally havingthe amino acid sequence of SEQ ID NO:106 and/or at least one light chainvariable region, optionally having the amino acid sequence of SEQ IDNO:116. Antibodies that bind to human IL-23 and that comprise a definedheavy or light chain variable region can be prepared using suitablemethods, such as phage display (Katsube, Y., et al., Int J Mol. Med,1(5):863-868 (1998)) or methods that employ transgenic animals, as knownin the art and/or as described herein. For example, a transgenic mouse,comprising a functionally rearranged human immunoglobulin heavy chaintransgene and a transgene comprising DNA from a human immunoglobulinlight chain locus that can undergo functional rearrangement, can beimmunized with human IL-23 or a fragment thereof to elicit theproduction of antibodies. If desired, the antibody producing cells canbe isolated and hybridomas or other immortalized antibody-producingcells can be prepared as described herein and/or as known in the art.Alternatively, the antibody, specified portion or variant can beexpressed using the encoding nucleic acid or portion thereof in asuitable host cell.

The invention also relates to antibodies, antigen-binding fragments,immunoglobulin chains and CDRs comprising amino acids in a sequence thatis substantially the same as an amino acid sequence described herein.Preferably, such antibodies or antigen-binding fragments and antibodiescomprising such chains or CDRs can bind human IL-23 with high affinity(e.g., K_(D) less than or equal to about 10⁻⁹M). Amino acid sequencesthat are substantially the same as the sequences described hereininclude sequences comprising conservative amino acid substitutions, aswell as amino acid deletions and/or insertions. A conservative aminoacid substitution refers to the replacement of a first amino acid by asecond amino acid that has chemical and/or physical properties (e.g.,charge, structure, polarity, hydrophobicity/hydrophilicity) that aresimilar to those of the first amino acid. Conservative substitutionsinclude, without limitation, replacement of one amino acid by anotherwithin the following groups: lysine (K), arginine (R) and histidine (H);aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine(S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine(V), leucine (L), isoleucine (I), proline (P), phenylalanine (F),tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W andY; C, S and T.

Amino Acid Codes

The amino acids that make up anti-IL-23 antibodies of the presentinvention are often abbreviated. The amino acid designations can beindicated by designating the amino acid by its single letter code, itsthree letter code, name, or three nucleotide codon(s) as is wellunderstood in the art (see Alberts, B., et al., Molecular Biology of TheCell, Third Ed., Garland Publishing, Inc., New York, 1994):

TABLE 19 SINGLE LETTER THREE THREE NUCLEOTIDE CODE LETTER CODE NAMECODON(S) A Ala Alanine GCA, GCC, GCG, GCU C Cys Cysteine UGC, UGU D AspAspartic acid GAC, GAU E Glu Glutamic acid GAA, GAG F Phe PhenylanineUUC, UUU G Gly Glycine GGA, GGC, GGG, GGU H His Histidine CAC, CAU I IleIsoleucine AUA, AUC, AUU K Lys Lysine AAA, AAG L Leu Leucine UUA, UUG,CUA, CUC, CUG, CUU M Met Methionine AUG N Asn Asparagine AAC, AAU P ProProline CCA, CCC, CCG, CCU Q Gln Glutamine CAA, CAG R Arg Arginine AGA,AGG, CGA, CGC, CGG, CGU S Ser Serine AGC, AGU, UCA, UCC, UCG, UCU T ThrThreonine ACA, ACC, ACG, ACU V Val Valine GUA, GUC, GUG, GUU W TrpTryptophan UGG Y Tyr Tyrosine UAC, UAUAn anti-IL-23 antibody used in the method of the present invention caninclude one or more amino acid substitutions, deletions or additions,either from natural mutations or human manipulation, as specifiedherein.

The number of amino acid substitutions a skilled artisan would makedepends on many factors, including those described above. Generallyspeaking, the number of amino acid substitutions, insertions ordeletions for any given anti-IL-23 antibody, fragment or variant willnot be more than 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9,8, 7, 6, 5, 4, 3, 2, 1, such as 1-30 or any range or value therein, asspecified herein.

Amino acids in an anti-IL-23 specific antibody that are essential forfunction can be identified by methods known in the art, such assite-directed mutagenesis or alanine-scanning mutagenesis (e.g.,Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science244:1081-1085 (1989)). The latter procedure introduces single alaninemutations at every residue in the molecule. The resulting mutantmolecules are then tested for biological activity, such as, but notlimited to, at least one IL-23 neutralizing activity. Sites that arecritical for antibody binding can also be identified by structuralanalysis, such as crystallization, nuclear magnetic resonance orphotoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992)and de Vos, et al., Science 255:306-312 (1992)).

Anti-IL-23 antibodies can include, but are not limited to, at least oneportion, sequence or combination selected from 5 to all of thecontiguous amino acids of at least one of SEQ ID NOS: 5, 20, 44, 50, 56,and 73.

IL-23 antibodies or specified portions or variants can include, but arenot limited to, at least one portion, sequence or combination selectedfrom at least 3-5 contiguous amino acids of the SEQ ID NOs above; 5-17contiguous amino acids of the SEQ ID NOs above, 5-10 contiguous aminoacids of the SEQ ID NOs above, 5-11 contiguous amino acids of the SEQ IDNOs above, 5-7 contiguous amino acids of the SEQ ID NOs above; 5-9contiguous amino acids of the SEQ ID NOs above.

An anti-IL-23 antibody can further optionally comprise a polypeptide ofat least one of 70-100% of 5, 17, 10, 11, 7, 9, 119, or 108 contiguousamino acids of the SEQ ID NOs above. In one embodiment, the amino acidsequence of an immunoglobulin chain, or portion thereof (e.g., variableregion, CDR) has about 70-100% identity (e.g., 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the aminoacid sequence of the corresponding chain of at least one of the SEQ IDNOs above. For example, the amino acid sequence of a light chainvariable region can be compared with the sequence of the SEQ ID NOsabove, or the amino acid sequence of a heavy chain CDR3 can be comparedwith the SEQ ID NOs above. Preferably, 70-100% amino acid identity(i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or valuetherein) is determined using a suitable computer algorithm, as known inthe art.

“Identity,” as known in the art, is a relationship between two or morepolypeptide sequences or two or more polynucleotide sequences, asdetermined by comparing the sequences. In the art, “identity” also meansthe degree of sequence relatedness between polypeptide or polynucleotidesequences, as determined by the match between strings of such sequences.“Identity” and “similarity” can be readily calculated by known methods,including, but not limited to, those described in ComputationalMolecular Biology, Lesk, A. M., ed., Oxford University Press, New York,1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed.,Academic Press, New York, 1993; Computer Analysis of Sequence Data, PartI, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey,1994; Sequence Analysis in Molecular Biology, von Heinje, G., AcademicPress, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux,J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman,D., Siam J. Applied Math., 48:1073 (1988). In addition, values forpercentage identity can be obtained from amino acid and nucleotidesequence alignments generated using the default settings for the AlignXcomponent of Vector NTI Suite 8.0 (Informax, Frederick, Md.).

Preferred methods to determine identity are designed to give the largestmatch between the sequences tested. Methods to determine identity andsimilarity are codified in publicly available computer programs.Preferred computer program methods to determine identity and similaritybetween two sequences include, but are not limited to, the GCG programpackage (Devereux, J., et al., Nucleic Acids Research 12(1): 387(1984)), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec.Biol. 215:403-410 (1990)). The BLAST X program is publicly availablefrom NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBINLMNIH Bethesda, Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403-410(1990). The well-known Smith Waterman algorithm may also be used todetermine identity.

Preferred parameters for polypeptide sequence comparison include thefollowing:

(1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970)Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl.Acad. Sci, USA. 89:10915-10919 (1992)

Gap Penalty: 12

Gap Length Penalty: 4

A program useful with these parameters is publicly available as the“gap” program from Genetics Computer Group, Madison Wis. Theaforementioned parameters are the default parameters for peptidesequence comparisons (along with no penalty for end gaps).

Preferred parameters for polynucleotide comparison include thefollowing:

(1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970)

Comparison matrix: matches=+10, mismatch=0

Gap Penalty: 50

Gap Length Penalty: 3

Available as: The “gap” program from Genetics Computer Group, MadisonWis. These are the default parameters for nucleic acid sequencecomparisons.

By way of example, a polynucleotide sequence may be identical to anothersequence, that is 100% identical, or it may include up to a certaininteger number of nucleotide alterations as compared to the referencesequence. Such alterations are selected from the group consisting of atleast one nucleotide deletion, substitution, including transition andtransversion, or insertion, and wherein the alterations may occur at the5′ or 3′ terminal positions of the reference nucleotide sequence oranywhere between those terminal positions, interspersed eitherindividually among the nucleotides in the reference sequence or in oneor more contiguous groups within the reference sequence. The number ofnucleotide alterations is determined by multiplying the total number ofnucleotides in the sequence by the numerical percent of the respectivepercent identity (divided by 100) and subtracting that product from thetotal number of nucleotides in the sequence, or:

n.sub.n.ltorsim.x.sub.n-(x.sub.n.y),

wherein n.sub.n is the number of nucleotide alterations, x.sub.n is thetotal number of nucleotides in sequence, and y is, for instance, 0.70for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%, etc.,and wherein any non-integer product of x.sub.n and y is rounded down tothe nearest integer prior to subtracting from x.sub.n.

Alterations of a polynucleotide sequence encoding the SEQ ID NOs abovemay create nonsense, missense or frameshift mutations in this codingsequence and thereby alter the polypeptide encoded by the polynucleotidefollowing such alterations. Similarly, a polypeptide sequence may beidentical to the reference sequence of the SEQ ID NOs above, that is be100% identical, or it may include up to a certain integer number ofamino acid alterations as compared to the reference sequence such thatthe percentage identity is less than 100%. Such alterations are selectedfrom the group consisting of at least one amino acid deletion,substitution, including conservative and non-conservative substitution,or insertion, and wherein the alterations may occur at the amino- orcarboxy-terminal positions of the reference polypeptide sequence oranywhere between those terminal positions, interspersed eitherindividually among the amino acids in the reference sequence or in oneor more contiguous groups within the reference sequence. The number ofamino acid alterations for a given % identity is determined bymultiplying the total number of amino acids in the SEQ ID NOs above bythe numerical percent of the respective percent identity (divided by100) and then subtracting that product from the total number of aminoacids in the SEQ ID NOs above, or:

n.sub.a.ltorsim.x.sub.a-(x.sub.a.y),

wherein n.sub.a is the number of amino acid alterations, x.sub.a is thetotal number of amino acids in the SEQ ID NOs above, and y is, forinstance 0.70 for 70%, 0.80 for 80%, 0.85 for 85% etc., and wherein anynon-integer produce of x.sub.a and y is rounded down to the nearestinteger prior to subtracting it from x.sub.a.

Exemplary heavy chain and light chain variable regions sequences andportions thereof are provided in the SEQ ID NOs above. The antibodies ofthe present invention, or specified variants thereof, can comprise anynumber of contiguous amino acid residues from an antibody of the presentinvention, wherein that number is selected from the group of integersconsisting of from 10-100% of the number of contiguous residues in ananti-IL-23 antibody. Optionally, this subsequence of contiguous aminoacids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 ormore amino acids in length, or any range or value therein. Further, thenumber of such subsequences can be any integer selected from the groupconsisting of from 1 to 20, such as at least 2, 3, 4, or 5.

As those of skill will appreciate, the present invention includes atleast one biologically active antibody of the present invention.Biologically active antibodies have a specific activity at least 20%,30%, or 40%, and, preferably, at least 50%, 60%, or 70%, and, mostpreferably, at least 80%, 90%, or 95%-100% or more (including, withoutlimitation, up to 10 times the specific activity) of that of the native(non-synthetic), endogenous or related and known antibody. Methods ofassaying and quantifying measures of enzymatic activity and substratespecificity are well known to those of skill in the art.

In another aspect, the invention relates to human antibodies andantigen-binding fragments, as described herein, which are modified bythe covalent attachment of an organic moiety. Such modification canproduce an antibody or antigen-binding fragment with improvedpharmacokinetic properties (e.g., increased in vivo serum half-life).The organic moiety can be a linear or branched hydrophilic polymericgroup, fatty acid group, or fatty acid ester group. In particularembodiments, the hydrophilic polymeric group can have a molecular weightof about 800 to about 120,000 Daltons and can be a polyalkane glycol(e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)),carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, andthe fatty acid or fatty acid ester group can comprise from about eightto about forty carbon atoms.

The modified antibodies and antigen-binding fragments can comprise oneor more organic moieties that are covalently bonded, directly orindirectly, to the antibody. Each organic moiety that is bonded to anantibody or antigen-binding fragment of the invention can independentlybe a hydrophilic polymeric group, a fatty acid group or a fatty acidester group. As used herein, the term “fatty acid” encompassesmono-carboxylic acids and di-carboxylic acids. A “hydrophilic polymericgroup,” as the term is used herein, refers to an organic polymer that ismore soluble in water than in octane. For example, polylysine is moresoluble in water than in octane. Thus, an antibody modified by thecovalent attachment of polylysine is encompassed by the invention.Hydrophilic polymers suitable for modifying antibodies of the inventioncan be linear or branched and include, for example, polyalkane glycols(e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like),carbohydrates (e.g., dextran, cellulose, oligosaccharides,polysaccharides and the like), polymers of hydrophilic amino acids(e.g., polylysine, polyarginine, polyaspartate and the like), polyalkaneoxides (e.g., polyethylene oxide, polypropylene oxide and the like) andpolyvinyl pyrolidone. Preferably, the hydrophilic polymer that modifiesthe antibody of the invention has a molecular weight of about 800 toabout 150,000 Daltons as a separate molecular entity. For example,PEG₅₀₀₀ and PEG_(20,000), wherein the subscript is the average molecularweight of the polymer in Daltons, can be used. The hydrophilic polymericgroup can be substituted with one to about six alkyl, fatty acid orfatty acid ester groups. Hydrophilic polymers that are substituted witha fatty acid or fatty acid ester group can be prepared by employingsuitable methods. For example, a polymer comprising an amine group canbe coupled to a carboxylate of the fatty acid or fatty acid ester, andan activated carboxylate (e.g., activated with N, N-carbonyldiimidazole) on a fatty acid or fatty acid ester can be coupled to ahydroxyl group on a polymer.

Fatty acids and fatty acid esters suitable for modifying antibodies ofthe invention can be saturated or can contain one or more units ofunsaturation. Fatty acids that are suitable for modifying antibodies ofthe invention include, for example, n-dodecanoate (Cu, laurate),n-tetradecanoate (C₁₄, myristate), n-octadecanoate (C₁₈, stearate),n-eicosanoate (C₂₀, arachidate), n-docosanoate (C₂₂, behenate),n-triacontanoate (C₃₀), n-tetracontanoate (C₄₀), cis-Δ9-octadecanoate(C₁₈, oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C₂₀, arachidonate),octanedioic acid, tetradecanedioic acid, octadecanedioic acid,docosanedioic acid, and the like. Suitable fatty acid esters includemono-esters of dicarboxylic acids that comprise a linear or branchedlower alkyl group. The lower alkyl group can comprise from one to abouttwelve, preferably, one to about six, carbon atoms.

The modified human antibodies and antigen-binding fragments can beprepared using suitable methods, such as by reaction with one or moremodifying agents. A “modifying agent” as the term is used herein, refersto a suitable organic group (e.g., hydrophilic polymer, a fatty acid, afatty acid ester) that comprises an activating group. An “activatinggroup” is a chemical moiety or functional group that can, underappropriate conditions, react with a second chemical group therebyforming a covalent bond between the modifying agent and the secondchemical group. For example, amine-reactive activating groups includeelectrophilic groups, such as tosylate, mesylate, halo (chloro, bromo,fluoro, iodo), N-hydroxysuccinimidyl esters (NETS), and the like.Activating groups that can react with thiols include, for example,maleimide, iodoacetyl, acrylolyl, pyridyl disulfides,5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. An aldehydefunctional group can be coupled to amine- or hydrazide-containingmolecules, and an azide group can react with a trivalent phosphorousgroup to form phosphoramidate or phosphorimide linkages. Suitablemethods to introduce activating groups into molecules are known in theart (see for example, Hermanson, G. T., Bioconjugate Techniques,Academic Press: San Diego, Calif. (1996)). An activating group can bebonded directly to the organic group (e.g., hydrophilic polymer, fattyacid, fatty acid ester), or through a linker moiety, for example, adivalent C₁-C₁₂ group wherein one or more carbon atoms can be replacedby a heteroatom, such as oxygen, nitrogen or sulfur. Suitable linkermoieties include, for example, tetraethylene glycol, —(CH₂)₃—,—NH—(CH₂)₆—NH—, —(CH₂)₂—NH— and —CH₂—O—CH₂—CH₂—O—CH₂—CH₂O—CH—NH—.Modifying agents that comprise a linker moiety can be produced, forexample, by reacting a mono-Boc-alkyldiamine (e.g.,mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid inthe presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) toform an amide bond between the free amine and the fatty acidcarboxylate. The Boc protecting group can be removed from the product bytreatment with trifluoroacetic acid (TFA) to expose a primary amine thatcan be coupled to another carboxylate, as described, or can be reactedwith maleic anhydride and the resulting product cyclized to produce anactivated maleimido derivative of the fatty acid. (See, for example,Thompson, et al., WO 92/16221, the entire teachings of which areincorporated herein by reference.)

The modified antibodies can be produced by reacting a human antibody orantigen-binding fragment with a modifying agent. For example, theorganic moieties can be bonded to the antibody in a non-site specificmanner by employing an amine-reactive modifying agent, for example, anNHS ester of PEG. Modified human antibodies or antigen-binding fragmentscan also be prepared by reducing disulfide bonds (e.g., intra-chaindisulfide bonds) of an antibody or antigen-binding fragment. The reducedantibody or antigen-binding fragment can then be reacted with athiol-reactive modifying agent to produce the modified antibody of theinvention. Modified human antibodies and antigen-binding fragmentscomprising an organic moiety that is bonded to specific sites of anantibody of the present invention can be prepared using suitablemethods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem.,3:147-153 (1992); Werlen et al., Bioconjugate Chem., 5:411-417 (1994);Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh et al.,Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al., Biotechnol.Bioeng., 56(4):456-463 (1997)), and the methods described in Hermanson,G. T., Bioconjugate Techniques, Academic Press: San Diego, Calif.(1996).

The method of the present invention also uses an anti-IL-23 antibodycomposition comprising at least one, at least two, at least three, atleast four, at least five, at least six or more anti-IL-23 antibodiesthereof, as described herein and/or as known in the art that areprovided in a non-naturally occurring composition, mixture or form. Suchcompositions comprise non-naturally occurring compositions comprising atleast one or two full length, C- and/or N-terminally deleted variants,domains, fragments, or specified variants, of the anti-IL-23 antibodyamino acid sequence selected from the group consisting of 70-100% of thecontiguous amino acids of the SEQ ID NOs above, or specified fragments,domains or variants thereof. Preferred anti-IL-23 antibody compositionsinclude at least one or two full length, fragments, domains or variantsas at least one CDR or LBP containing portions of the anti-IL-23antibody sequence described herein, for example, 70-100% of the SEQ IDNOs above, or specified fragments, domains or variants thereof. Furtherpreferred compositions comprise, for example, 40-99% of at least one of70-100% of the SEQ ID NOs above, etc., or specified fragments, domainsor variants thereof. Such composition percentages are by weight, volume,concentration, molarity, or molality as liquid or dry solutions,mixtures, suspension, emulsions, particles, powder, or colloids, asknown in the art or as described herein.

Antibody Compositions Comprising Further Therapeutically ActiveIngredients

The antibody compositions used in the method of the invention canoptionally further comprise an effective amount of at least one compoundor protein selected from at least one of an anti-infective drug, acardiovascular (CV) system drug, a central nervous system (CNS) drug, anautonomic nervous system (ANS) drug, a respiratory tract drug, agastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid orelectrolyte balance, a hematologic drug, an antineoplastic, animmunomodulation drug, an ophthalmic, otic or nasal drug, a topicaldrug, a nutritional drug or the like. Such drugs are well known in theart, including formulations, indications, dosing and administration foreach presented herein (see, e.g., Nursing 2001 Handbook of Drugs,21^(st) edition, Springhouse Corp., Springhouse, P A, 2001; HealthProfessional's Drug Guide 2001, ed., Shannon, Wilson, Stang,Prentice-Hall, Inc, Upper Saddle River, N.J.; Pharmcotherapy Handbook,Wells et al., ed., Appleton & Lange, Stamford, Conn., each entirelyincorporated herein by reference).

By way of example of the drugs that can be combined with the antibodiesfor the method of the present invention, the anti-infective drug can beat least one selected from amebicides or at least one antiprotozoals,anthelmintics, antifungals, antimalarials, antituberculotics or at leastone antileprotics, aminoglycosides, penicillins, cephalosporins,tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolideanti-infectives, and miscellaneous anti-infectives. The hormonal drugcan be at least one selected from corticosteroids, androgens or at leastone anabolic steroid, estrogen or at least one progestin, gonadotropin,antidiabetic drug or at least one glucagon, thyroid hormone, thyroidhormone antagonist, pituitary hormone, and parathyroid-like drug. The atleast one cephalosporin can be at least one selected from cefaclor,cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride,cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium,cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoximeproxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium,ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexinhydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

The at least one coricosteroid can be at least one selected frombetamethasone, betamethasone acetate or betamethasone sodium phosphate,betamethasone sodium phosphate, cortisone acetate, dexamethasone,dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisoneacetate, hydrocortisone, hydrocortisone acetate, hydrocortisonecypionate, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, prednisolone, prednisolone acetate,prednisolone sodium phosphate, prednisolone tebutate, prednisone,triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. Theat least one androgen or anabolic steroid can be at least one selectedfrom danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate,nandrolone phenpropionate, testosterone, testosterone cypionate,testosterone enanthate, testosterone propionate, and testosteronetransdermal system.

The at least one immunosuppressant can be at least one selected fromazathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immuneglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetilhydrochloride, sirolimus, and tacrolimus.

The at least one local anti-infective can be at least one selected fromacyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazolenitrate, clindamycin phosphate, clotrimazole, econazole nitrate,erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate,metronidazole (topical), miconazole nitrate, mupirocin, naftifinehydrochloride, neomycin sulfate, nitrofurazone, nystatin, silversulfadiazine, terbinafine hydrochloride, terconazole, tetracyclinehydrochloride, tioconazole, and tolnaftate. The at least one scabicideor pediculicide can be at least one selected from crotamiton, lindane,permethrin, and pyrethrins. The at least one topical corticosteroid canbe at least one selected from betamethasone dipropionate, betamethasonevalerate, clobetasol propionate, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate,fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasonepropionate, halcionide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocorisone valerate, mometasone furoate, andtriamcinolone acetonide. (See, e.g., pp. 1098-1136 of Nursing 2001 DrugHandbook.)

Anti-IL-23 antibody compositions can further comprise at least one ofany suitable and effective amount of a composition or pharmaceuticalcomposition comprising at least one anti-IL-23 antibody contacted oradministered to a cell, tissue, organ, animal or patient in need of suchmodulation, treatment or therapy, optionally further comprising at leastone selected from at least one TNF antagonist (e.g., but not limited toa TNF chemical or protein antagonist, TNF monoclonal or polyclonalantibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) orfragment, fusion polypeptides thereof, or a small molecule TNFantagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II),nerelimonmab, infliximab, eternacept, CDP-571, CDP-870, afelimomab,lenercept, and the like), an antirheumatic (e.g., methotrexate,auranofin, aurothioglucose, azathioprine, etanercept, gold sodiumthiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a cytokine or a cytokineantagonist. Non-limiting examples of such cytokines include, but are notlimited to, any of IL-1 to IL-23 et al. (e.g., IL-1, IL-2, etc.).Suitable dosages are well known in the art. See, e.g., Wells et al.,eds., Pharmacotherapy Handbook, 2^(nd) Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),each of which references are entirely incorporated herein by reference.

Anti-IL-23 antibody compounds, compositions or combinations used in themethod of the present invention can further comprise at least one of anysuitable auxiliary, such as, but not limited to, diluent, binder,stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvantor the like. Pharmaceutically acceptable auxiliaries are preferred.Non-limiting examples of, and methods of preparing such sterilesolutions are well known in the art, such as, but limited to, Gennaro,Ed., Remington's Pharmaceutical Sciences, 18^(th) Edition, MackPublishing Co. (Easton, Pa.) 1990. Pharmaceutically acceptable carrierscan be routinely selected that are suitable for the mode ofadministration, solubility and/or stability of the anti-IL-23 antibody,fragment or variant composition as well known in the art or as describedherein.

Pharmaceutical excipients and additives useful in the presentcomposition include, but are not limited to, proteins, peptides, aminoacids, lipids, and carbohydrates (e.g., sugars, includingmonosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatizedsugars, such as alditols, aldonic acids, esterified sugars and the like;and polysaccharides or sugar polymers), which can be present singly orin combination, comprising alone or in combination 1-99.99% by weight orvolume. Exemplary protein excipients include serum albumin, such ashuman serum albumin (HSA), recombinant human albumin (rHA), gelatin,casein, and the like. Representative amino acid/antibody components,which can also function in a buffering capacity, include alanine,glycine, arginine, betaine, histidine, glutamic acid, aspartic acid,cysteine, lysine, leucine, isoleucine, valine, methionine,phenylalanine, aspartame, and the like. One preferred amino acid isglycine.

Carbohydrate excipients suitable for use in the invention include, forexample, monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), myoinositol and the like. Preferred carbohydrateexcipients for use in the present invention are mannitol, trehalose, andraffinose.

Anti-IL-23 antibody compositions can also include a buffer or a pHadjusting agent; typically, the buffer is a salt prepared from anorganic acid or base. Representative buffers include organic acid salts,such as salts of citric acid, ascorbic acid, gluconic acid, carbonicacid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris,tromethamine hydrochloride, or phosphate buffers. Preferred buffers foruse in the present compositions are organic acid salts, such as citrate.

Additionally, anti-IL-23 antibody compositions can include polymericexcipients/additives, such as polyvinylpyrrolidones, ficolls (apolymeric sugar), dextrates (e.g., cyclodextrins, such as2-hydroxypropyl-β-cyclodextrin), polyethylene glycols, flavoring agents,antimicrobial agents, sweeteners, antioxidants, antistatic agents,surfactants (e.g., polysorbates, such as “TWEEN 20” and “TWEEN 80”),lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol),and chelating agents (e.g., EDTA).

These and additional known pharmaceutical excipients and/or additivessuitable for use in the anti-IL-23 antibody, portion or variantcompositions according to the invention are known in the art, e.g., aslisted in “Remington: The Science & Practice of Pharmacy,” 19^(th) ed.,Williams & Williams, (1995), and in the “Physician's Desk Reference,”52^(nd) ed., Medical Economics, Montvale, N.J. (1998), the disclosuresof which are entirely incorporated herein by reference. Preferredcarrier or excipient materials are carbohydrates (e.g., saccharides andalditols) and buffers (e.g., citrate) or polymeric agents. An exemplarycarrier molecule is the mucopolysaccharide, hyaluronic acid, which maybe useful for intraarticular delivery.

Formulations

As noted above, the invention provides for stable formulations, whichpreferably comprise a phosphate buffer with saline or a chosen salt, aswell as preserved solutions and formulations containing a preservativeas well as multi-use preserved formulations suitable for pharmaceuticalor veterinary use, comprising at least one anti-IL-23 antibody in apharmaceutically acceptable formulation. Preserved formulations containat least one known preservative or optionally selected from the groupconsisting of at least one phenol, m-cresol, p-cresol, o-cresol,chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol,formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate),alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkoniumchloride, benzethonium chloride, sodium dehydroacetate and thimerosal,or mixtures thereof in an aqueous diluent. Any suitable concentration ormixture can be used as known in the art, such as 0.001-5%, or any rangeor value therein, such as, but not limited to 0.001, 0.003, 0.005,0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range orvalue therein. Non-limiting examples include, no preservative, 0.1-2%m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol(e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g.,0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9,1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002,0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5,0.75, 0.9, 1.0%), and the like.

As noted above, the method of the invention uses an article ofmanufacture, comprising packaging material and at least one vialcomprising a solution of at least one anti-IL-23 specific antibody withthe prescribed buffers and/or preservatives, optionally in an aqueousdiluent, wherein said packaging material comprises a label thatindicates that such solution can be held over a period of 1, 2, 3, 4, 5,6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or greater.The invention further uses an article of manufacture, comprisingpackaging material, a first vial comprising lyophilized anti-IL-23specific antibody, and a second vial comprising an aqueous diluent ofprescribed buffer or preservative, wherein said packaging materialcomprises a label that instructs a patient to reconstitute theanti-IL-23 specific antibody in the aqueous diluent to form a solutionthat can be held over a period of twenty-four hours or greater.

The anti-IL-23 specific antibody used in accordance with the presentinvention can be produced by recombinant means, including from mammaliancell or transgenic preparations, or can be purified from otherbiological sources, as described herein or as known in the art.

The range of the anti-IL-23 specific antibody includes amounts yieldingupon reconstitution, if in a wet/dry system, concentrations from about1.0 μg/ml to about 1000 mg/ml, although lower and higher concentrationsare operable and are dependent on the intended delivery vehicle, e.g.,solution formulations will differ from transdermal patch, pulmonary,transmucosal, or osmotic or micro pump methods.

Preferably, the aqueous diluent optionally further comprises apharmaceutically acceptable preservative. Preferred preservativesinclude those selected from the group consisting of phenol, m-cresol,p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl,ethyl, propyl, butyl and the like), benzalkonium chloride, benzethoniumchloride, sodium dehydroacetate and thimerosal, or mixtures thereof. Theconcentration of preservative used in the formulation is a concentrationsufficient to yield an anti-microbial effect. Such concentrations aredependent on the preservative selected and are readily determined by theskilled artisan.

Other excipients, e.g., isotonicity agents, buffers, antioxidants, andpreservative enhancers, can be optionally and preferably added to thediluent. An isotonicity agent, such as glycerin, is commonly used atknown concentrations. A physiologically tolerated buffer is preferablyadded to provide improved pH control. The formulations can cover a widerange of pHs, such as from about pH 4 to about pH 10, and preferredranges from about pH 5 to about pH 9, and a most preferred range ofabout 6.0 to about 8.0. Preferably, the formulations of the presentinvention have a pH between about 6.8 and about 7.8. Preferred buffersinclude phosphate buffers, most preferably, sodium phosphate,particularly, phosphate buffered saline (PBS).

Other additives, such as a pharmaceutically acceptable solubilizers likeTween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40(polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene(20) sorbitan monooleate), Pluronic F68 (polyoxyethylenepolyoxypropylene block copolymers), and PEG (polyethylene glycol) ornon-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or188, Pluronic® polyls, other block co-polymers, and chelators, such asEDTA and EGTA, can optionally be added to the formulations orcompositions to reduce aggregation. These additives are particularlyuseful if a pump or plastic container is used to administer theformulation. The presence of pharmaceutically acceptable surfactantmitigates the propensity for the protein to aggregate.

The formulations can be prepared by a process which comprises mixing atleast one anti-IL-23 specific antibody and a preservative selected fromthe group consisting of phenol, m-cresol, p-cresol, o-cresol,chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl,butyl and the like), benzalkonium chloride, benzethonium chloride,sodium dehydroacetate and thimerosal or mixtures thereof in an aqueousdiluent. Mixing the at least one anti-IL-23 specific antibody andpreservative in an aqueous diluent is carried out using conventionaldissolution and mixing procedures. To prepare a suitable formulation,for example, a measured amount of at least one anti-IL-23 specificantibody in buffered solution is combined with the desired preservativein a buffered solution in quantities sufficient to provide the proteinand preservative at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The formulations can be provided to patients as clear solutions or asdual vials comprising a vial of lyophilized anti-IL-23 specific antibodythat is reconstituted with a second vial containing water, apreservative and/or excipients, preferably, a phosphate buffer and/orsaline and a chosen salt, in an aqueous diluent. Either a singlesolution vial or dual vial requiring reconstitution can be reusedmultiple times and can suffice for a single or multiple cycles ofpatient treatment and thus can provide a more convenient treatmentregimen than currently available.

The present articles of manufacture are useful for administration over aperiod ranging from immediate to twenty-four hours or greater.Accordingly, the presently claimed articles of manufacture offersignificant advantages to the patient. Formulations of the invention canoptionally be safely stored at temperatures of from about 2° C. to about40° C. and retain the biologically activity of the protein for extendedperiods of time, thus allowing a package label indicating that thesolution can be held and/or used over a period of 6, 12, 18, 24, 36, 48,72, or 96 hours or greater. If preserved diluent is used, such label caninclude use up to 1-12 months, one-half, one and a half, and/or twoyears.

The solutions of anti-IL-23 specific antibody can be prepared by aprocess that comprises mixing at least one antibody in an aqueousdiluent. Mixing is carried out using conventional dissolution and mixingprocedures. To prepare a suitable diluent, for example, a measuredamount of at least one antibody in water or buffer is combined inquantities sufficient to provide the protein and, optionally, apreservative or buffer at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The claimed products can be provided to patients as clear solutions oras dual vials comprising a vial of lyophilized at least one anti-IL-23specific antibody that is reconstituted with a second vial containingthe aqueous diluent. Either a single solution vial or dual vialrequiring reconstitution can be reused multiple times and can sufficefor a single or multiple cycles of patient treatment and thus provides amore convenient treatment regimen than currently available.

The claimed products can be provided indirectly to patients by providingto pharmacies, clinics, or other such institutions and facilities, clearsolutions or dual vials comprising a vial of lyophilized at least oneanti-IL-23 specific antibody that is reconstituted with a second vialcontaining the aqueous diluent. The clear solution in this case can beup to one liter or even larger in size, providing a large reservoir fromwhich smaller portions of the at least one antibody solution can beretrieved one or multiple times for transfer into smaller vials andprovided by the pharmacy or clinic to their customers and/or patients.

Recognized devices comprising single vial systems include pen-injectordevices for delivery of a solution, such as BD Pens, BD Autojector®,Humaject®, NovoPen®, B-D® Pen, AutoPen®, and OptiPen®, GenotropinPen®,Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®,Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject®e.g., as made or developed by Becton Dickensen (Franklin Lakes, N.J.,www.bectondickenson.com), Disetronic (Burgdorf, Switzerland,www.disetronic.com; Bioject, Portland, Oreg. (www.bioject.com); NationalMedical Products, Weston Medical (Peterborough, UK,www.weston-medical.com), Medi-Ject Corp (Minneapolis, Minn.,www.mediject.com), and similary suitable devices. Recognized devicescomprising a dual vial system include those pen-injector systems forreconstituting a lyophilized drug in a cartridge for delivery of thereconstituted solution, such as the HumatroPen®. Examples of otherdevices suitable include pre-filled syringes, auto-injectors, needlefree injectors, and needle free IV infusion sets.

The products may include packaging material. The packaging materialprovides, in addition to the information required by the regulatoryagencies, the conditions under which the product can be used. Thepackaging material of the present invention provides instructions to thepatient, as applicable, to reconstitute the at least one anti-IL-23antibody in the aqueous diluent to form a solution and to use thesolution over a period of 2-24 hours or greater for the two vial,wet/dry, product. For the single vial, solution product, pre-filledsyringe or auto-injector, the label indicates that such solution can beused over a period of 2-24 hours or greater. The products are useful forhuman pharmaceutical product use.

The formulations used in the method of the present invention can beprepared by a process that comprises mixing an anti-IL-23 antibody and aselected buffer, preferably, a phosphate buffer containing saline or achosen salt. Mixing the anti-IL-23 antibody and buffer in an aqueousdiluent is carried out using conventional dissolution and mixingprocedures. To prepare a suitable formulation, for example, a measuredamount of at least one antibody in water or buffer is combined with thedesired buffering agent in water in quantities sufficient to provide theprotein and buffer at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The method of the invention provides pharmaceutical compositionscomprising various formulations useful and acceptable for administrationto a human or animal patient. Such pharmaceutical compositions areprepared using water at “standard state” as the diluent and routinemethods well known to those of ordinary skill in the art. For example,buffering components such as histidine and histidine monohydrochloridehydrate, may be provided first followed by the addition of anappropriate, non-final volume of water diluent, sucrose and polysorbate80 at “standard state.” Isolated antibody may then be added. Last, thevolume of the pharmaceutical composition is adjusted to the desiredfinal volume under “standard state” conditions using water as thediluent. Those skilled in the art will recognize a number of othermethods suitable for the preparation of the pharmaceutical compositions.

The pharmaceutical compositions may be aqueous solutions or suspensionscomprising the indicated mass of each constituent per unit of watervolume or having an indicated pH at “standard state.” As used herein,the term “standard state” means a temperature of 25° C.+/−2° C. and apressure of 1 atmosphere. The term “standard state” is not used in theart to refer to a single art recognized set of temperatures or pressure,but is instead a reference state that specifies temperatures andpressure to be used to describe a solution or suspension with aparticular composition under the reference “standard state” conditions.This is because the volume of a solution is, in part, a function oftemperature and pressure. Those skilled in the art will recognize thatpharmaceutical compositions equivalent to those disclosed here can beproduced at other temperatures and pressures. Whether suchpharmaceutical compositions are equivalent to those disclosed hereshould be determined under the “standard state” conditions defined above(e.g. 25° C.+/−2° C. and a pressure of 1 atmosphere).

Importantly, such pharmaceutical compositions may contain componentmasses “about” a certain value (e.g. “about 0.53 mg L-histidine”) perunit volume of the pharmaceutical composition or have pH values about acertain value. A component mass present in a pharmaceutical compositionor pH value is “about” a given numerical value if the isolated antibodypresent in the pharmaceutical composition is able to bind a peptidechain while the isolated antibody is present in the pharmaceuticalcomposition or after the isolated antibody has been removed from thepharmaceutical composition (e.g., by dilution). Stated differently, avalue, such as a component mass value or pH value, is “about” a givennumerical value when the binding activity of the isolated antibody ismaintained and detectable after placing the isolated antibody in thepharmaceutical composition.

Competition binding analysis is performed to determine if the IL-23specific mAbs bind to similar or different epitopes and/or compete witheach other. Abs are individually coated on ELISA plates. Competing mAbsare added, followed by the addition of biotinylated hrIL-23. Forpositive control, the same mAb for coating may be used as the competingmAb (“self-competition”). IL-23 binding is detected using streptavidin.These results demonstrate whether the mAbs recognize similar orpartially overlapping epitopes on IL-23.

One aspect of the method of the invention administers to a patient apharmaceutical composition comprising

In one embodiment of the pharmaceutical compositions, the isolatedantibody concentration is from about 77 to about 104 mg per ml of thepharmaceutical composition. In another embodiment of the pharmaceuticalcompositions the pH is from about 5.5 to about 6.5.

The stable or preserved formulations can be provided to patients asclear solutions or as dual vials comprising a vial of lyophilized atleast one anti-IL-23 antibody that is reconstituted with a second vialcontaining a preservative or buffer and excipients in an aqueousdiluent. Either a single solution vial or dual vial requiringreconstitution can be reused multiple times and can suffice for a singleor multiple cycles of patient treatment and thus provides a moreconvenient treatment regimen than currently available.

Other formulations or methods of stabilizing the anti-IL-23 antibody mayresult in other than a clear solution of lyophilized powder comprisingthe antibody. Among non-clear solutions are formulations comprisingparticulate suspensions, said particulates being a compositioncontaining the anti-IL-23 antibody in a structure of variable dimensionand known variously as a microsphere, microparticle, nanoparticle,nanosphere, or liposome. Such relatively homogenous, essentiallyspherical, particulate formulations containing an active agent can beformed by contacting an aqueous phase containing the active agent and apolymer and a nonaqueous phase followed by evaporation of the nonaqueousphase to cause the coalescence of particles from the aqueous phase astaught in U.S. Pat. No. 4,589,330. Porous microparticles can be preparedusing a first phase containing active agent and a polymer dispersed in acontinuous solvent and removing said solvent from the suspension byfreeze-drying or dilution-extraction-precipitation as taught in U.S.Pat. No. 4,818,542. Preferred polymers for such preparations are naturalor synthetic copolymers or polymers selected from the group consistingof gleatin agar, starch, arabinogalactan, albumin, collagen,polyglycolic acid, polylactic aced, glycolide-L(−) lactidepoly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lactic acid),poly(epsilon-caprolactone-CO-glycolic acid), poly(β-hydroxy butyricacid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate),poly(hydroxyethyl methacrylate), polyamides, poly(amino acids),poly(2-hydroxyethyl DL-aspartamide), poly(ester urea),poly(L-phenylalanine/ethylene glycol/1,6-diisocyanatohexane) andpoly(methyl methacrylate). Particularly preferred polymers arepolyesters, such as polyglycolic acid, polylactic aced, glycolide-L(−)lactide poly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lacticacid), and poly(epsilon-caprolactone-CO-glycolic acid. Solvents usefulfor dissolving the polymer and/or the active include: water,hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane,benzene, or hexafluoroacetone sesquihydrate. The process of dispersingthe active containing phase with a second phase may include pressureforcing said first phase through an orifice in a nozzle to affectdroplet formation.

Dry powder formulations may result from processes other thanlyophilization, such as by spray drying or solvent extraction byevaporation or by precipitation of a crystalline composition followed byone or more steps to remove aqueous or nonaqueous solvent. Preparationof a spray-dried antibody preparation is taught in U.S. Pat. No.6,019,968. The antibody-based dry powder compositions may be produced byspray drying solutions or slurries of the antibody and, optionally,excipients, in a solvent under conditions to provide a respirable drypowder. Solvents may include polar compounds, such as water and ethanol,which may be readily dried. Antibody stability may be enhanced byperforming the spray drying procedures in the absence of oxygen, such asunder a nitrogen blanket or by using nitrogen as the drying gas. Anotherrelatively dry formulation is a dispersion of a plurality of perforatedmicrostructures dispersed in a suspension medium that typicallycomprises a hydrofluoroalkane propellant as taught in WO 9916419. Thestabilized dispersions may be administered to the lung of a patientusing a metered dose inhaler. Equipment useful in the commercialmanufacture of spray dried medicaments are manufactured by Buchi Ltd. orNiro Corp.

An anti-IL-23 antibody in either the stable or preserved formulations orsolutions described herein, can be administered to a patient inaccordance with the present invention via a variety of delivery methodsincluding SC or IM injection; transdermal, pulmonary, transmucosal,implant, osmotic pump, cartridge, micro pump, or other means appreciatedby the skilled artisan, as well-known in the art.

Therapeutic Applications

The present invention also provides a method for modulating or treatingpsoriasis, in a cell, tissue, organ, animal, or patient, as known in theart or as described herein, using at least one IL-23 antibody of thepresent invention, e.g., administering or contacting the cell, tissue,organ, animal, or patient with a therapeutic effective amount of IL-23specific antibody.

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising an anti-IL-23 antibody to a cell, tissue, organ, animal orpatient in need of such modulation, treatment or therapy. Such a methodcan optionally further comprise co-administration or combination therapyfor treating such diseases or disorders, wherein the administering ofsaid at least one anti-IL-23 antibody, specified portion or variantthereof, further comprises administering, before concurrently, and/orafter, at least one selected from at least one TNF antagonist (e.g., butnot limited to, a TNF chemical or protein antagonist, TNF monoclonal orpolyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70or p85) or fragment, fusion polypeptides thereof, or a small moleculeTNF antagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II),nerelimonmab, infliximab, eternacept (Enbrel™), adalimulab (Humira™),CDP-571, CDP-870, afelimomab, lenercept, and the like), an antirheumatic(e.g., methotrexate, auranofin, aurothioglucose, azathioprine, goldsodium thiomalate, hydroxychloroquine sulfate, leflunomide,sulfasalzine), a muscle relaxant, a narcotic, a non-steroidanti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative,a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g.,aminoglycoside, an antifungal, an antiparasitic, an antiviral, acarbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin,a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic,a corticosteriod, an anabolic steroid, a diabetes related agent, amineral, a nutritional, a thyroid agent, a vitamin, a calcium relatedhormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer,a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), afilgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a growth hormone, a hormonereplacement drug, an estrogen receptor modulator, a mydriatic, acycloplegic, an alkylating agent, an antimetabolite, a mitoticinhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, anantipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, astimulant, donepezil, tacrine, an asthma medication, a beta agonist, aninhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn,an epinephrine or analog, dornase alpha (Pulmozyme), a cytokine or acytokine antagonist. Suitable dosages are well known in the art. See,e.g., Wells et al., eds., Pharmacotherapy Handbook, 2^(nd) Edition,Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, TarasconPocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, LomaLinda, C A (2000); Nursing 2001 Handbook of Drugs, 21^(st) edition,Springhouse Corp., Springhouse, P A, 2001; Health Professional's DrugGuide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, UpperSaddle River, N.J., each of which references are entirely incorporatedherein by reference.

Therapeutic Treatments

Typically, treatment of psoriasis is affected by administering aneffective amount or dosage of an anti-IL-23 antibody composition thattotal, on average, a range from at least about 0.01 to 500 milligrams ofan anti-IL-23 antibody per kilogram of patient per dose, and,preferably, from at least about 0.1 to 100 milligrams antibody/kilogramof patient per single or multiple administration, depending upon thespecific activity of the active agent contained in the composition.Alternatively, the effective serum concentration can comprise 0.1-5000μg/ml serum concentration per single or multiple administrations.Suitable dosages are known to medical practitioners and will, of course,depend upon the particular disease state, specific activity of thecomposition being administered, and the particular patient undergoingtreatment. In some instances, to achieve the desired therapeutic amount,it can be necessary to provide for repeated administration, i.e.,repeated individual administrations of a particular monitored or metereddose, where the individual administrations are repeated until thedesired daily dose or effect is achieved.

Preferred doses can optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and/or 100-500mg/kg/administration, or any range, value or fraction thereof, or toachieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9,2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5,6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11,11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5,5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10,10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5,15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19,19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,and/or 5000 μg/ml serum concentration per single or multipleadministration, or any range, value or fraction thereof.

Alternatively, the dosage administered can vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adosage of active ingredient can be about 0.1 to 100 milligrams perkilogram of body weight. Ordinarily 0.1 to 50, and, preferably, 0.1 to10 milligrams per kilogram per administration or in sustained releaseform is effective to obtain desired results.

As a non-limiting example, treatment of humans or animals can beprovided as a one-time or periodic dosage of at least one antibody ofthe present invention 0.1 to 100 mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100mg/kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or, alternatively oradditionally, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, or 52, or, alternatively or additionally, at least oneof 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 years, or any combination thereof, using single, infusion or repeateddoses.

Dosage forms (composition) suitable for internal administrationgenerally contain from about 0.001 milligram to about 500 milligrams ofactive ingredient per unit or container. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-99.999% by weight based on the total weight of thecomposition.

For parenteral administration, the antibody can be formulated as asolution, suspension, emulsion, particle, powder, or lyophilized powderin association, or separately provided, with a pharmaceuticallyacceptable parenteral vehicle. Examples of such vehicles are water,saline, Ringer's solution, dextrose solution, and 1-10% human serumalbumin. Liposomes and nonaqueous vehicles, such as fixed oils, can alsobe used. The vehicle or lyophilized powder can contain additives thatmaintain isotonicity (e.g., sodium chloride, mannitol) and chemicalstability (e.g., buffers and preservatives). The formulation issterilized by known or suitable techniques.

Suitable pharmaceutical carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, A. Osol, a standardreference text in this field.

Alternative Administration

Many known and developed modes can be used according to the presentinvention for administering pharmaceutically effective amounts of ananti-IL-23 antibody. While pulmonary administration is used in thefollowing description, other modes of administration can be usedaccording to the present invention with suitable results. IL-23 specificantibodies of the present invention can be delivered in a carrier, as asolution, emulsion, colloid, or suspension, or as a dry powder, usingany of a variety of devices and methods suitable for administration byinhalation or other modes described here within or known in the art.

Parenteral Formulations and Administration

Formulations for parenteral administration can contain as commonexcipients sterile water or saline, polyalkylene glycols, such aspolyethylene glycol, oils of vegetable origin, hydrogenated naphthalenesand the like. Aqueous or oily suspensions for injection can be preparedby using an appropriate emulsifier or humidifier and a suspending agent,according to known methods. Agents for injection can be a non-toxic,non-orally administrable diluting agent, such as aqueous solution, asterile injectable solution or suspension in a solvent. As the usablevehicle or solvent, water, Ringer's solution, isotonic saline, etc. areallowed; as an ordinary solvent or suspending solvent, sterileinvolatile oil can be used. For these purposes, any kind of involatileoil and fatty acid can be used, including natural or synthetic orsemisynthetic fatty oils or fatty acids; natural or synthetic orsemisynthtetic mono- or di- or tri-glycerides. Parental administrationis known in the art and includes, but is not limited to, conventionalmeans of injections, a gas pressured needle-less injection device asdescribed in U.S. Pat. No. 5,851,198, and a laser perforator device asdescribed in U.S. Pat. No. 5,839,446 entirely incorporated herein byreference.

Alternative Delivery

The invention further relates to the administration of an anti-IL-23antibody by parenteral, subcutaneous, intramuscular, intravenous,intrarticular, intrabronchial, intraabdominal, intracapsular,intracartilaginous, intracavitary, intracelial, intracerebellar,intracerebroventricular, intracolic, intracervical, intragastric,intrahepatic, intramyocardial, intraosteal, intrapelvic,intrapericardiac, intraperitoneal, intrapleural, intraprostatic,intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal,intrasynovial, intrathoracic, intrauterine, intravesical, intralesional,bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermalmeans. An anti-IL-23 antibody composition can be prepared for use forparenteral (subcutaneous, intramuscular or intravenous) or any otheradministration particularly in the form of liquid solutions orsuspensions; for use in vaginal or rectal administration particularly insemisolid forms, such as, but not limited to, creams and suppositories;for buccal, or sublingual administration, such as, but not limited to,in the form of tablets or capsules; or intranasally, such as, but notlimited to, the form of powders, nasal drops or aerosols or certainagents; or transdermally, such as not limited to a gel, ointment,lotion, suspension or patch delivery system with chemical enhancers suchas dimethyl sulfoxide to either modify the skin structure or to increasethe drug concentration in the transdermal patch (Junginger, et al. In“Drug Permeation Enhancement;” Hsieh, D. S., Eds., pp. 59-90 (MarcelDekker, Inc. New York 1994, entirely incorporated herein by reference),or with oxidizing agents that enable the application of formulationscontaining proteins and peptides onto the skin (WO 98/53847), orapplications of electric fields to create transient transport pathways,such as electroporation, or to increase the mobility of charged drugsthrough the skin, such as iontophoresis, or application of ultrasound,such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the abovepublications and patents being entirely incorporated herein byreference).

Method of Selling and/or Promoting

The invention further relates to a method of selling and/or promoting anapproved pharmaceutical product (by the US FDA or equivalent ex-USregulatory agency) comprising an antibody to IL-23, such as an antibodydescribed herein, e.g., guselkumab, comprising advertising, promotingand/or otherwise highlighting in connection with sales of guselkumab(Tremfya®) the superiority of clinical endpoint results at week 44and/or week 48 from initial treatment after continuous treatment withthe antibody to IL-23 versus clinical endpoint results at week 44 and/orweek 48 from initial treatment after continuous treatment withsecukinumab in treated psoriasis patients.

Having generally described the invention, the same will be more readilyunderstood by reference to the following Examples, which are provided byway of illustration and are not intended as limiting. Further details ofthe invention are illustrated by the following non-limiting Examples.The disclosures of all citations in the specification are expresslyincorporated herein by reference.

Example 1: A Phase 3, Multicenter, Randomized, Double-Blind StudyEvaluating the Comparative Efficacy of CNTO 1959 (Guselkumab) andSecukinumab for the Treatment of Moderate to Severe Plaque-Type Psorisis

Study Design:

-   -   A Phase 3, randomized, double-blind, multicenter,        active-comparator-controlled study in subjects with moderate to        severe plaque-type psoriasis with 2 parallel treatment groups:        guselkumab 100 mg and secukinumab 300 mg.    -   Randomization: At Week 0, approximately 1040 subjects who        satisfy all inclusion and exclusion criteria were planned to be        randomized in a 1:1 ratio to 1 of 2 arms based on permuted block        randomization with stratification by study site:        -   Group I (n=520): guselkumab 100 mg SC at Weeks 0, 4, 12, 20,            and q8w thereafter through Week 44.        -   Group II (n=520): secukinumab 300 mg SC at Weeks 0, 1, 2, 3,            4, and q4w thereafter through Week 44.    -   Treatment duration/Trial duration: Week 44 was the last dosing        visit; subjects were followed for an additional 12 weeks after        Week 44, with a final safety visit at Week 56. The end of the        study was defined as the time when last subject completes the        Week 56 visit. There was 1 database lock (DBL) in this study at        Week 56.

A schematic of the study is shown below in Table 4.

TABLE 4 Overview of the Study Randomization Week Guselkumab 100 mg SC (n= 520) Secukinumab 300 mg SC (n = 520) 0 Guselkumab (one 100 mginjection + Placebo Secukinumab (two 150 mg injections) (one injection)1 Placebo (two injections) Secukinumab (two 150 mg injections) 2 Placebo(two injections) Secukinumab (two 150 mg injections) 3 Placebo (twoinjections) Secukinumab (two 150 mg injections) 4 Guselkumab (one 100 mginjection + Placebo Secukinumab (two 150 mg injections) (one injection)8 Placebo (two injections) Secukinumab (two 150 mg injections) 12Guselkiunab (one 100 mg injection + Placebo Secukinumab (two 150 mginjections) (one injection) 16 Placebo (two injections) Secukinumab (two150 mg injections) 20 Guselkumab (one 100 mg injection + PlaceboSecukinumab (two 150 mg injections) (one injection) 24 Placebo (twoinjections) Secukinumab (two 150 mg injections) 28 Guselkumab (one 100mg injection + Placebo Secukinumab (two 150 mg injections) (oneinjection) 32 Placebo (two injections) Secukinumab (two 150 mginjections) 36 Guselkumab (one 100 mg injection + Placebo Secukinumab(two 150 mg injections) (one injection) 40 Placebo (two injections)Secukinumab (two 150 mg injections) 44 Guselkumab (one 100 mginjection + Placebo Secukinumab (two 150 mg injections) (one injection)48 Primary Endpoint 56 Database Lock

-   -   Primary analysis set for efficacy: The primary efficacy analysis        included all randomized subjects according to subjects' assigned        treatment at Week 0, regardless of the treatment they actually        received. This is also referred to as the full analysis set        (FAS). The full analysis set was also used for all secondary        efficacy analyses.    -   Primary endpoint: the proportion of subjects who achieved a PASI        90 response at Week 48 (non-inferiority test followed by        superiority)    -   Major secondary efficacy variables: There were 6 major secondary        endpoints in this study:        -   The proportion of subjects who achieved a PASI 75 response            at both Week 12 and Week 48 (non-inferiority test followed            by superiority)        -   The proportion of subjects who achieved a PASI 90 response            at Week 12 (non-inferiority)        -   The proportion of subjects who achieved a PASI 75 response            at Week 12 (non-inferiority)        -   The proportion of subjects who achieved a PASI 100 response            at Week 48 (non-inferiority test followed by superiority)        -   The proportion of subjects who achieved an IGA score of            cleared (0) at Week 48 (non-inferiority test followed by            superiority)        -   The proportion of subjects who achieved an IGA score of            cleared (0) or minimal (1) at Week 48 (non-inferiority test            followed by superiority)        -   Non-inferiority margin was set to be 10% for all endpoints.    -   To control the overall Type 1 error rate, it was specified that        the primary analyses and major secondary analyses would be        tested in a fixed sequence as ordered above. That is, the first        major secondary endpoint would be tested only if the primary        endpoint was positive, and the subsequent endpoint(s) would be        tested only if the preceding endpoint in the sequence was        positive.    -   Planned sample size and power: A total of approximately 1,040        subjects randomized in a 1:1 ratio was expected to detect the        differences between guselkumab group and secukinumab group with        at least 92% power for PASI 90 response rate at Week 48 at a        2-sided significance level of 0.05. The assumptions for the        sample size and power calculations, based on the data from the        guselkumab CNTO1959PS03001 and CNTO1959PS03002 and the        secukinumab Phase 3 studies (ERASURE and FIXTURE), were:        -   PASI 90 response rate at Week 48 was 70% to 80% for            guselkumab group and 60% to 70% for secukinumab group.

Based on the above assumptions, the planned sample size, and anoninferiority margin of 10%, the power to demonstrate thenon-inferiority for the primary endpoint of PASI 90 at Week 48 would be>99%.

Primary Objective(s):

The primary objective is to evaluate the efficacy of guselkumab comparedwith secukinumab for the treatment of subjects with moderate to severeplaque-type psoriasis

Topline Results Summary

CNTO1959PSO3009 is a Phase 3, randomized, double-blind, multicenter,active-comparator-controlled study in subjects with moderate to severeplaque psoriasis, defined by a IGA≥3, PASI≥12, and BSA involvement of atleast 10%, who were candidates for or previously received eithersystemic therapy or phototherapy. This database lock includes all datathrough Week 56 for all randomized subjects.

A total of 1200 subjects were screened of which 1048 subjects wererandomized into guselkumab (n=534) or secukinumab (n=514) treatmentgroups. The study was conducted at 141 sites in 9 countries: Australia,Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and theUS. The treatment groups were well balanced for baseline demographic andpsoriasis characteristics. The majority of the subjects were white(93.4%) and male (67.5%). The median age was 46.0 years, and meanbaseline weight was 89.2 kg (Appendix 1). Three subjects randomized tothe secukinumab group did not receive any study agent due to violationof a study entry criterion. These 3 subjects were included in allefficacy analyses but excluded from the safety analyses.

Baseline disease characteristics were generally comparable between thetreatment groups. The median duration of psoriasis was 16.1 years. Themedian percent of body surface area (BSA) involved was 20.0, with amedian PASI score of 18.0. In addition, 76.1% subjects presented with anIGA=3, and 23.8% of subjects had severe disease as defined by theirbaseline IGA score of 4 (Appendix 2).

The proportions of subjects receiving previous therapies in eachprevious psoriasis medication category were comparable between thetreatment groups. Overall, 51.8% previously received phototherapy, 53.7%previously received systemic therapy and 29.1% previously receivedbiologic therapy. Overall, 37.1% of subjects were naïve to non-biologicsystemic and biologic therapies (Appendix 3).

The key baseline demographics, psoriasis disease characteristics andprevious psoriasis medications/therapies are summarized in Table 1.

TABLE 1 Summary of Important Baseline Demographic, PSO Characteristics,and Previous Psoriasis Medications and Therapies by Medication CategoryGuselkumab Secukinumab Total Analysis set: Subjects in full analysis set534 514 1048 Weight (kg) (Mean) 89.3 89.1 89.2 PSO Characteristics BSA(Mean) 23.7 24.5 24.1 PASI Score (0-72) (Mean) 20.0 20.1 20.0 IGA scoreMild (2) 0 0.2% 0.1% Moderate (3) 76.2% 76.1% 76.1% Severe (4) 23.8%23.7% 23.8% Previous Psoriasis Medications and Therapies Phototherapy(PUVA or UVB) 52.6% 50.9% 51.8% Non-biologic systemics 51.7% 55.8% 53.7%Biologics 29.2% 29.0% 29.1% Naïve to non-biologic systemics and 38.6%35.6% 37.1% biologicsThrough Week 44, 5.1% of subjects in the guselkumab group and 9.3% ofsubjects in the secukinumab group discontinued study agent. The mostcommon reason for study agent discontinuation was adverse event (1.7%)and withdrawal by subject (1.3%) in the guselkumab group, and withdrawalby subject (3.7%) and adverse events (2.1%) in the secukinumab group(Appendix 4).Primary Efficacy Endpoints:Significantly greater proportions of subjects in the guselkumab groupachieved a PASI 90 response at Week 48 (84.5%) than in the secukinumabgroup (70.0%) (p-value <0.001) (Table 2).

TABLE 2 Number of PASI 90 Responders at Week 48 (Superiority Analysis);Full Analysis Set (Study CNTO1959PSO3009) Guselkumab SecukinumabAnalysis set: Full analysis set 534 514 PASI 90 responders 451 (84.5%)360 (70.0%) Treatment differences (95% CI) 14.2% (9.6%, 18.8%) p-value<0.001 Note 1: Treatment difference and 95% CI were calculated adjustingfor investigator site (pooled) using MH weights. Note 2: P-value wasbased on CMH chi-square test stratified by the investigator site(pooled)Major Secondary Efficacy Endpoints:

-   -   Guselkumab is non-inferior to secukinumab for the proportion of        subjects who achieved a PASI 75 response at both Week 12 and        Week 48 [84.6% (guselknumab) vs. 80.2% (secukinumab); 95% CI:        (−0.2%, 8.9%); p<0.001] (Appendix 6); however, though the        response rate of guselkumab group was numerically higher than        that of the secukinumab group, the superiority test was not        significant (p=0.062) (Appendix 7). Therefore, because of the        stipulation that the primary analyses and major secondary        analyses would be tested in a fixed sequence to control the        overall Type 1 error rate, the p-values reported for the rest of        the major secondary endpoints are considered nominal.    -   Non-inferiority for the proportion of subjects who achieved a        PASI 90 response at Week 12 was not demonstrated [69.1%        (guselknumab) vs. 76.1% (secukinumab); 95% CI: (−12.2%, −1.7%);        p=0.127] (Appendix 8).    -   Guselkumab is non-inferior to secukinumab as assessed by the        proportion of subjects who achieved a PASI 75 response at Week        12 [89.3% (guselkunumab) vs. 91.6% (secukinumab); 95% CI:        (−6.0%, 1.2%); p<0.001] (Appendix 9).    -   The proportion of subjects who achieved a PASI 100 response at        Week 48 was significantly higher in the guselkumab group        compared to the secukinumab group [58.2% (guselkunumab) vs.        48.4% (secukinumab); p=0.001)] (Appendix 10).    -   The proportion of subjects who achieved an IGA score of        cleared (0) at Week 48 was significantly higher in the        guselkumab group compared to the secukinumab group [62.2%        (guselkunumab) vs. 50.4% (secukinumab); p<0.001] (Appendix 11).    -   The proportion of subjects who achieved an IGA score of        cleared (0) or minimal (1) at Week 48 was significantly higher        in the guselkumab group compared to the secukinumab group [85.0%        (guselkunumab) vs. 74.9% (secukinumab); p<0.001] (Appendix 12).        Other Efficacy Endpoints:    -   The proportion of subjects who achieved a PASI 90 response at        all 7 visits from Week 24 through Week 48 was significantly        higher in the guselkumab group compared to the secukinumab group        [71.0% (guselkunumab) vs. 61.5% (secukinumab); p<0.001]        (Appendix 13).    -   IGA and PASI responses over time    -   The proportions of subjects achieving a PASI 90 response, a PASI        100 response, an IGA score of cleared (0), and an IGA score of        cleared (0) or minimal (1) over time from Week 1 through Week 48        are summarized in FIG. 1A FIG. 1D (also see Appendix 14 and 15).    -   These curves highlight differences in the rate and maintenance        of response over time between guselkumab and secukinumab. The        PASI 90 figure panel, for example, shows that responses start        occurring for both treatments at Weeks 2 and 3. Between Weeks 3        and 12, secukinumab PASI 90 response rates are higher than those        for guselkumab. At Weeks 16 and 20, both drugs show similar PASI        90 response rates, and PASI 90 response rates for guselkumab are        higher than those for secukinumab at all visits from Week 24        through Week 48. The guselkumab PASI 90 response rate curve        reaches a plateau at Week 28, and then the response rate remains        stable through Week 48. In contrast, the PASI 90 response rate        curve for secukinumab plateaus earlier, at Week 20, and the        response rate then declines steadily from Week 20 through        Week 48. For the other 3 endpoints, the patterns of response        rates are similar to that of PASI 90, although there is        variability in the timing of when response rates plateau, and        the visits at which the switch from higher response rates for        secukinumab to higher rates for guselkumab occur.        Safety:        Safety was assessed among all randomized and treated subjects        who received at least 1 dose of study agent (partial or        complete) according to the actual treatment received during the        study, irrespective of the treatment assigned at randomization.        This is also referred to as the safety analysis set. Key safety        events are summarized in Table 3.

TABLE 3 Key safety events; treated subjects Guselkumab SecukinumabAnalysis set: Safety analysis set 534 511 Avg duration of follow-up(weeks) 54.90 53.67 Avg exposure (number of 14.65 14.41administrations)^(a) Avg number of active injections 6.8 28.8 receivedSubjects who discontinued study 10 (1.9%) 12 (2.3%) agent because of 1or more adverse events Subjects with 1 or more: Adverse events 416(77.9%) 417 (81.6%) Serious adverse events 33 (6.2%) 37 (7.2%) Overallinfections 313 (58.6%) 331 (64.8%) Infections requiring treatment 118(22.1%) 147 (28.8%) Serious infections 6 (1.1%) 5 (1.0%) Malignancy 7(1.3%) 4 (0.8%) NMSC 6 (1.1%) 2 (0.4%) Other malignancy 1 (0.2%) 2(0.4%) MACE^(b) 0 1 (0.2%) Suicidal ideation or behavior^(c) 8 (1.5%) 8(1.6%) Inflammatory bowel disease^(d) 0 3 (0.6%) Anaphylactic reactionor serum 0 0 sickness-like reaction to active study agent ISR to activestudy agent^(e) 13 (2.4%) 20 (3.9%) Total number of active injections3644 14722 Active injections with ISR 19 (0.5%) 63 (0.4%) ^(a)Alladministrations were counted regardless of whether they are active orplacebo injections. Each administration includes two injections.^(b)MACE: investigator reported nonfatal myocardial infarction (MI),nonfatal stroke or CV death. One stroke (PT: cerebrovascular accident)was reported in the secukinumab group. ^(c)Suicidal ideation andbehavior data was collected by electronic Columbia-Suicide SeverityRating Scale (eC-SSRS) at scheduled visits. When suicidal ideation orbehavior-related adverse events occurred outside of a study visit, theywere reported on the AE eCRF. ^(d)Preferred terms of IBD: Crohn'sdisease and inflammatory bowel disease ^(e)ISR: injection site reactions

-   -   The proportion of subjects experiencing 1 or more adverse events        categorized as infections by the investigator was lower in the        guselkumab group compared with the secukinumab group (58.6%        [313/534] in the guselkumab group, 64.8% [331/511] in the        secukinumab group) (Appendix 19).        -   The most common infections were PTs of nasopharyngitis            [21.9% (guselkumab) vs. 24.5% (secukinumab)] and upper            respiratory tract infection [15.5% (guselkumab) vs. 18.0%            (secukinumab)].        -   Individual PTs representing fungal infections reported            in >2% of subjects included tinea pedis (1.1% vs. 3.1%),            oral candidiasis (0.9% vs. 2.2%) and vulvovaginal            candidiasis (0.9% vs 2.5%) for the guselkumab and            secukinumab groups.        -   All serious infections were single events in both treatment            groups and there was no pattern or trend for either            treatment group. No cases of active tuberculosis or            opportunistic infections were reported during the study            (Appendix 21).    -   A total of 3 BCCs (0.6%) were reported in the guselkumab group        versus 2 BCCs (0.4%) in the secukinumab group.        -   Two skin squamous cell carcinomas and 1 Bowen's disease were            reported in the guselkumab group.    -   One subject in the guselkumab group was diagnosed with invasive        ductal breast carcinoma. One subject in the secukinumab group        was diagnosed with non-small cell lung cancer and another        subject was diagnosed with mycosis fungoides.    -   A total of 3 subjects in the secukinumab group reported an event        of Crohn's disease, IBD or colitis:        -   One subject, was diagnosed with a serious AE of Crohn's            disease. This subject received 5 scheduled doses of study            agent.        -   Two subjects reported a non-serious AE of IBD.            -   One subject, with a history of chronic IBD that was not                identified in screening was randomized and received 5                doses of study agent before being discontinued upon                confirmation of Crohn's colitis.                A second subject, approximately a month after completing                the 44 weeks of treatment presented with symptoms that                were suggestive of, and later confirmed to be Crohn's                disease.                Analysis of Patients with PsA

Post hoc analyses examined the subgroup of patients with self-reportedPsoriatic Arthritis (PsA). For the PsA subpopulation, treatmentdifferences and 95% confidence intervals (CIs) were calculated. Missingdata were imputed as non-response. Both efficacy and safety wereassessed through Week 56. Overall, treatment groups [GUS (n=534), SEC(n=514)] were comparable at baseline: weight 89 kg, 24% body surfacearea PsO, and Investigator Global Assessment (IGA) moderate (76%) orsevere (24%). These characteristics were similar to those of subgroupswith self-reported PsA [GUS (n=97), SEC (n=79)]. In the overallpopulation, the primary endpoint of PASI 90 response at Week 48 wasreached by 84.5% GUS patients vs 70.0% SEC patients (P<0.001). Resultsof the first major secondary endpoint (proportion of patients with aPASI 75 response at both Week 12 and 48) showed non-inferiority of GUSvs SEC (GUS-84.6% vs SEC-80.2% of patients, p<0.001), but superioritywas not demonstrated (p=0.062). Among patients with PsA, the primaryendpoint of Week-48 PASI 90 response was reached by 82.5% GUS vs 63.3%SEC patients (treatment difference 19.2% [95% CI=5.0, 33.4]). In boththe overall population and the subgroup of patients with PsA, peak PASI90 response rates were achieved between Weeks 16 and 24 for both drugs.GUS-treated patients sustained this response through Week 48, whereasSEC patients demonstrated reduction in response rate from Weeks 24 to48. Adverse events observed in the overall population were generallyconsistent with the established safety profiles for GUS and SEC. Safetyresults among patients with PsA were consistent with that of the overallpopulation. In the subset of patients with self-reported PsA in theECLIPSE study, GUS demonstrated higher long-term efficacy andmaintenance of response compared with SEC in the treatment of moderateto severe plaque PsO, consistent with the overall trial population withplaque PsO.

Weight Quartile Analysis

Efficacy data were analyzed by baseline body weight quartiles (Q1, ≤74kg; Q2, >74 to ≤87 kg; Q3, >87 to ≤100 kg; Q4, >100 kg) and BMIcategories (normal, <25 kg/m²; overweight, ≥25 to <30 kg/m²; obese, ≥30kg/m²). This post-hoc analysis evaluated efficacy by baseline bodyweight quartiles and body mass index (BMI) categories. There were nobody weight restrictions for enrollment in the study.

The data are shown in Tables 12-16 below. Missing data were imputed asnon-response after applying treatment failure rules. The proportions ofpatients achieving a PASI90 response at Week48 in the guselkumab andsecukinumab groups, respectively were as follows: by baseline bodyweight quartiles—Q1, 86.7% vs 75.6% (11.1% [0.9%-21.3%]); Q2, 89.1% vs73.0% (16.0% [6.0%-26.0%]); Q3, 80.3% vs 71.0% (9.3% [−1.9%-20.6%]); Q4,82.1% vs 61.3% (20.9% [9.4%-32.3%]); by BMI categories-normal, 88.1% vs75.2% (12.8% [2.2%-23.5%]); overweight, 84.1% vs 73.4% (10.6%[1.6%-19.7%]); obese, 82.5% vs 65.3% (17.2% [8.8%-25.6%]) (percentdifference [95% CI]). These results are consistent with the primaryendpoint of PASI90 at Week 48 in the overall study population(guselkumab, 84.5% vs secukinumab, 70.0% [14.2% (9.2%-19.2%)]). Similarresults were observed across all body weight quartiles and BMIcategories for PASI100, IGA0, and IGA0/1 responses, with allbetween-treatment differences numerically favoring guselkumab. Inconclusion, across baseline body weight quartiles and BMI categories,efficacy outcome response rates at Week48 were consistently numericallygreater for guselkumab compared to secukinumab in the treatment ofmoderate to severe psoriasis.

Body Region Analysis

As shown in Table 17, guselkumab showed numerically greater levels ofefficacy than secukinumab through 48 weeks in body region components ofthe PASI, including head and neck, trunk, and upper and lowerextremities, compared with secukinumab in the treatment of moderate tosevere psoriasis. Improvement in body region components of PASI,including the head and neck, trunk, and upper and lower extremities, wasalso evaluated. Missing data were imputed as nonresponse.

At Week 48, numerically greater proportions of patients achievedimprovement (100% improvement and ≥90% improvement) with guselkumab thanwith secukinumab for the PASI components of head and neck, trunk, andupper and lower extremities (Table 17).

Patient Geographic Area Analysis

Patients from North America (United States, Canada; n=391), EasternEurope (Czech Republic, Hungary, Poland; n=338), Western Europe (France,Germany, Spain; n=248), and Australia (n=71) were randomized to receiveguselkumab 100 mg subcutaneous (SC) at Weeks 0, 4, 12, then every 8weeks (n=534), or secukinumab 300 mg SC at Weeks 0, 1, 2, 3, 4, thenevery 4 weeks (n=514), both through Week 44. The primary endpoint wasthe proportion of patients achieving a PASI 90 response at Week 48.Missing data were imputed as nonresponse.

As shown in Table 18, regardless of geographic region, PASI 90 responserates with guselkumab treatment were higher at Week 48 compared withsecukinumab in the treatment of moderate to severe psoriasis. Subgroupanalyses by geographical region showed higher PASI 90 response ratesamong guselkumab-treated patients versus secukinumab-treated patients inall regions: North America (guselkumab 78.9% vs secukinumab 60.4%);Eastern Europe (guselkumab 90.6% vs secukinumab 76.0%); Western Europe(guselkumab 82.9% vs secukinumab 74.8%); and Australia (guselkumab 91.4%vs secukinumab 77.8%) (Table 18).

Example 2—Assessment of the Treatment Effect of Anti-IL-23 andAnti-IL-17A on Immune Cell Populations in Skin and Serum IL-17F andIL-22 Levels

Skin biopsies were collected at wks 0, 4 and 24. Skin gene expressionprofiles were generated in whole biopsy via RNAseq. The composition of Tcells was determined by immunophenotyping of cell suspensions fromdissociated biopsies using flow cytometry combined with unbiasedclustering analysis. Serum was collected at wks 0, 4, 24 and 48 andanalyzed by ultrasensitive immunoassays for IL17A, IL17F, IL22, IL23 andbeta defensin-2 (BD-2) levels. In addition, the numbers of CD4⁺ and CD8⁺T cells were measured in skin lesions.

Results

Serum IL17A, IL17F and IL22 levels were reduced at wks 4, 24, and 48after guselkumab treatment. In contrast, treatment with secukinumabreduced IL17F levels less efficiently than guselkumab (p<0.0001, alltimepoints) and had no effect on IL22 levels (free IL17A levels in SECcohort could not be measured with the assay used). Accordingly, therewas a greater reduction in serum levels of IL-17F and IL-22 fromguselkumab treatment versus secukinumab treatment at weeks 4, 24 and 48.

Reduction in levels of BD-2, a biomarker highly correlated with skininflammation, was greater with secukinumab vs guselkumab treatment at wk4 (p<0.0001), and was equivalent at wk 24; however, BD-2 increased insecukinumab arm but remained reduced in the guselkumab arm at wk 48(p<0.05) such that there was a greater reduction in BD-2 levels byguselkumab versus secukinumab at wk 48. Normalization of skintranscriptional changes was more pronounced in the secukinumab vsguselkumab group at wk 4, but equivalent at wk 24. Normalization ofincreased skin gene expression of IL17A, IL22 and IL23 was comparablebetween both treatments at wk 4 and 24, while expression of IL23R wassignificantly reduced by guselkumab only (p<0.01). At wk 24 oftreatment, the numbers of CD4⁺ and CD8⁺ T cells decreased in skinlesions in both cohorts. However, the frequency of CD8⁺ TRMs (CD3⁺,CD8⁺, CD103⁺ and/or CD49a⁺) decreased relative to baseline withguselkumab (p=0.036) but not with secukinumab. The reduction inIL17A⁺/CD8⁺TRMs in lesional skin did not differ between treatments. Incontrast, the frequency of regulatory T cells (Tregs) (FoxP3⁺, CD25⁺,IL17A⁻) was higher in the guselkumab arm at wk 24 (p=0.042).

Genes that are part of the psoriasis transcriptome that are betternormalized by GUS vs SEC, including IL23R were identified

Increased expression in PSO lesional skin of a group of genes associatedwith mucosal-associated invariant T cells (MAIT) (including IL23R) wasbetter normalized by GUS vs SEC at Week 24

Frequency of CD8+ tissue resident memory cells (TRMs) (CD3+, CD8+,CD103+ and/or CD49a+) was decreased relative to lesional baseline withGUS treatment (p<0.05) but not with SEC at week 24 Frequency ofregulatory T cells (Tregs) (CD3+, FoxP3+, CD25+, IL17A−) were higher inthe GUS arm compared to SEC arm at week 24 (p<0.05)

Analysis of IL-23+APC indicated that CD14+CD64+DC were responsible formajority of IL-23 expression in PsO lesional skin. Expansion of CD4 Tcells were associated with relative increase of non-TRM (CD103−CD49a−).Expansion of CD8 T cells were associated with relative increase in thefrequency of TRMs (CD103+ and/or CD49a+). A large increase in CD8 TRMsand non-TRMs and CD4 non TRMs in PsO SkinCD4+non-TRM and CD8+TRMs arethe major contributors of IL-17A in PsO (Baseline). The frequency ofTreg population in T cells is significantly increased in PsO lesions. 2distinct clusters of Tregs were identified, one IL17A+ and one IL17A-N.An increased frequency of IL17A expression within T cell subsets inlesional vs non-lesional skin. CD4+ T cells making IL-17A were mostlynon-TRMs while CD8+ T cells making IL-17A were mostly TRMs. Tregscontribute to a low amount of IL17A expression in PsO skin. A moresignificant decrease in the frequency of TRMs in CD8+ T cells inresponse to guselkumab vs secukinumab in cohort at wk 24. No differencein the frequency of TRMs in CD4+ T cell subsets in response toguselkumab vs secukinumab at wk 24. No difference in non-TRM CD4+ ornon-TRM CD8+ T cell subsets between guselkumab or secukinumab treatmentsat wk 24. IL17A was reduced significantly in guselkumab group(measurement in SEC cohort complicated by inability of assay todifferentiate SEC bound vs free IL17A resulting in increases in IL17A).An increased frequency of IL17A expression within CD8TRMs in lesionalskin at baseline seems to be associated with not achieving PASI>90 atweek 48 (regardless of treatment arm). No similar pattern observed innon lesional skin at baseline.

FIG. 2 shows the ECLIPSE study design through Week 48 and samplescollected for biomarker sub-studies. Blood samples for the serum proteinbiomarker sub-study were collected from all participated subjects atWeeks 0, 4, 24, and 48. Skin samples, including a pair of non-lesionalskin and lesional skin at Week 0, and lesional skin after Weeks 4 and24, were collected from a subset of subjects (19 GUS-treated and 16 SECtreated) for a skin transcriptome biomarker sub-study. Separately, skinsamples, including a pair of non-lesional skin and lesional skin at Week0, and lesional skin after Weeks 4 and 24, were collected from anothersubset of subjects (11 GUS-treated and 9 SEC treated) forimmunophenotyping of skin immune cells sub-study.

As shown in FIG. 3 , elevated serum levels of IL-17F in psoriasispatients were reduced by both treatments, with faster and greaterreduction by guselkumab. Compared to healthy controls (n=25), serumlevels of IL-17F were elevated in psoriasis patients (n=200), with 5.2fold and p<0.0001. Reduction in elevated serum IL-17F was greater inguselkumab treated samples (n=100) vs secukinumab treated samples(n=100) at all visits after week 4: 2.26 fold vs 1.12 fold, p<0.0001 atWeek 4; 5.32 fold vs 2.31 fold, p<0.0001 at Week 24; and 5.28 fold vs2.33 fold, p<0.0001 at Week 48. Serum IL-17F was normalized to the levelof healthy controls in guselkumab-treated patients at Weeks 24 and 48.LS Means: Least Squares Means; CI: confidence intervals. LS Means and95% CI were computed based on log transformed concentration using amixed-effects model with repeated-measures, where the treatment(guselkumab and secukinumab) and visits (Weeks 0, 4, 24, and 48) arefixed effects and subject is a random effect.

As shown in FIG. 4 , elevated serum levels of IL-22 in psoriasis werereduced by both treatments, with faster and greater reduction byguselkumab. Compared to healthy controls (n=25), serum levels of IL-22were elevated in psoriasis patients (n=200), with 6.0 fold and p<0.0001.Reduction in elevated serum IL-22 was greater by guselkumab (n=100) vssecukinumab (n=100) at all visits after week 4: 1.74 fold vs 1.28 fold,p=0.057 at Week 4; 2.79 fold vs 1.25 fold, p<0.0001 at Week 24; and 2.85fold vs 1.24 fold, p<0.0001 at Week 48.

LS Means: Least Squares Means; CI: confidence intervals. LS Means and95% CI were computed based on log transformed concentration using amixed-effects model with repeated-measures, where the treatment(guselkumab and secukinumab) and visits (Weeks 0, 4, 24, and 48) arefixed effects, and subject is a random effect.

As shown in FIG. 5 , elevated serum levels of beta defensin-2 (BD-2) inpsoriasis were reduced by both treatments, with faster reduction bysecukinumab but more sustained reduction by guselkumab. Compared tohealthy controls (n=25), serum levels of BD-2 were elevated in psoriasispatients (n=200), with >32 fold and p<0.0001. Reduction in elevatedserum BD-2 was greater with secukinumab (n=100) vs guselkumab (n=100)(13.1 fold vs 5.0 fold, p<0.0001) at Week 4, and was equivalent (18.4fold vs 17.3 fold, p=0.99) at Week 24, but was reversed (18.9 fold withguselkumab vs. 13.7 fold with secukinumab, p<0.05) at Week 48.

LS Means: Least Squares Means; CI: confidence intervals. LS Means and95% CI were computed based on log transformed concentration using amixed-effects model with repeated-measures, where the treatment(guselkumab and secukinumab) and visits (Weeks 0, 4, 24, and 48) arefixed effects, and subject is a random effect.

As shown in FIG. 6 , a subset of induced genes in psoriasis lesionalskin were better normalized by guselkumab than secukinumab at Week 24.Quantification of gene expression in individual skin biopsies werecomputed as log 2 transformed Transcripts per Million (TPM) from RNA-SeqDifferential gene expression between lesional skin (LS) and non-lesionalskin (NL) at baseline were calculated as the log 2 transformed ratiosbased on paired t test among 35 psoriasis patients. 1655 genes hadincreased expression in LS, with fold change >1.5 and false discoveryrate (FDR)<0.05. Differential gene expression in LS in response totreatment at Week 4 and 24 were computed as log 2 transformed ratiousing a mixed-effects model with repeated-measures, where the treatment(guselkumab and secukinumab) and visits (Weeks 4 and 24) are fixedeffects, subject is a random effect, and the differential geneexpression at baseline (between lesional skin and non-lesional skin) isa covariate. For a given gene, % of improvement in response to atreatment at a given visit is calculated as the negative ratio of thelog 2 transformed ratio for the response in LS vs the log 2 transformedratio of the difference between LS and NL at baseline. Among the 1655genes had increased expression in LS at baseline, 328 (19.8%) hadgreater improvement in response to guselkumab than secukinumab at Week24, as defined as >50% improvement in response to guselkumab, and >25%of difference in improvement between guselkumab vs secukinumab. Lightgrey lines represent individual genes, and the thick black linerepresents the average of % improvement among 328 genes in response toguselkumab (126%) vs secukinumab (76%). GUS: guselkumab, SEC:secukinumab

As shown in FIG. 7 , increased expression in psoriasis lesional skin ofa group of genes associated with mucosal-associated invariant T (MAIT)cells was better normalized by guselkumab than secukinumab at Week 24.Light grey lines represent individual genes. GUS: guselkumab, SEC:secukinumab.

PsO is a T cell driven disease where skin resident T cells that producemultiple inflammatory cytokines are believed to play an important rolein orchestrating the inflammatory immune response that leads toactivation and proliferation of keratinocytes and culminates inhyperkeratosis, erythema and scaling, hallmarks of PsO inflamed skin.Inflammatory T cells in the skin and other tissues are believed toexpress IL23R and are dependent on IL-23 for becoming immunopathogenic.To better understand the mechanism of action of guselkumab, we sought tocharacterize PsO skin T cells by flow cytometry-based immunophenotypingof cell suspensions from dissociated biopsies. Using this approach, weshowed that the frequency of CD8+ tissue resident memory T cells (TRMs)in lesional skin at week 24 was decreased relative to baseline levels inthe GUS cohort (p=0.036) but not in the secukinumab. This leads tohigher frequency of CD8 TRMs in the secukinumab cohort compared toguselkumab cohort at week 24 (p=0.0048).

TABLE 20 Summary of P values - Frequency of CD8 TRM within CD3 T cellsTreatment Week P values Guselkumab Week 0-NL vs Week 0-L 0.021683Guselkumab Week 0-NL vs Week 4 0.028696 Guselkumab Week 0-NL vs Week 240.83748 Guselkumab Week 0-L vs Week 4 0.909182 Guselkumab Week 0-L vsWeek 24 0.035655 Guselkumab Week 4 vs Week 24 0.046409 Secukinumab Week0-NL vs Week 0-L 0.800505 Secukinumab Week 0-NL vs Week 4 0.18244Secukinumab Week 0-NL vs Week 24 0.300364 Secukinumab Week 0-L vs Week 40.278196 Secukinumab Week 0-L vs Week 24 0.432394 Secukinumab Week 4 vsWeek 24 0.762684 Guselkumab vs Secukinumab 0-NL 0.048327 Guselkumab vsSecukinumab 0-L 0.961635 Guselkumab vs Secukinumab  4 0.196808Guselkumab vs Secukinumab 24 0.004842

As shown in FIG. 8 , the frequency of CD8 TRM in PSO skin was reduced byguselkumab, but not by secukinumab at Week 24. Characterization of PSOskin T cells was done by immunophenotyping of cell suspension obtainedfrom dissociated biopsy. Compared to baseline lesional skin, frequencyof CD8 TRMs (CD3⁺, CD8⁺, CD103⁺ and/or CD49a⁺) was reduced at Week 24 inthe guselkumab arm (n=11, p<0.05) but not in the secukinumab arm (n=9).Statistical analysis was performed using SAS 9.4 software usinglongitudinal regression model with difference from lesion at baseline asresponse, lesion at baseline as predictor, treatment and week as factorand interaction term between treatment and week, and AR1 as covariancestructure. Data was plotted as change from baseline lesion using leastsquare means and 95% confidence interval.

IL23 has also been reported to have an antagonistic effect on thefunction of regulatory T cells (Treg). Treg in PsO blood and skin havebeen reported to be increased but are defective in function. To betterunderstand the mechanism of action of guselkumab, we sought tocharacterize PsO skin T cells by flow cytometry-based immunophenotypingof cell suspensions from dissociated biopsies. Using this novelapproach, we showed that the frequency of Treg (CD3⁺, FoxP3⁺, CD25⁺) inthe GUS arm was maintained relative to baseline levels at week 24. Incomparison, in the cohort treated with secukinumab, the levels of Tregswere reduced relative to baseline at week 24 (p=0.00013). Thus, GUS wasable to maintain the relative frequency of Treg during the course oftreatment.

TABLE 21 Summary of P values - Frequency of Tregs within CD3 T cellsTreatment Week P values Guselkumab Week 0-NL vs Week 0-L 0.00704Guselkumab Week 0-NL vs Week 4 0.055978 Guselkumab Week 0-NL vs Week 240.065898 Guselkumab Week 0-L vs Week 4 0.408284 Guselkumab Week 0-L vsWeek 24 0.36752 Guselkumab Week 4 vs Week 24 0.94038 Secukinumab Week0-NL vs Week 0-L 8.3E−06 Secukinumab Week 0-NL vs Week 4 0.029787Secukinumab Week 0-NL vs Week 24 0.457042 Secukinumab Week 0-L vs Week 40.011765 Secukinumab Week 0-L vs Week 24 0.000126 Secukinumab Week 4 vsWeek 24 0.146146 Guselkumab vs Secukinumab 0-NL 0.346175 Guselkumab vsSecukinumab 0-L 0.161581 Guselkumab vs Secukinumab  4 0.636662Guselkumab vs Secukinumab 24 0.059004

As shown in FIG. 9 , the frequency of regulatory T cells (Tregs) wasreduced in the secukinumab arm but not in guselkumab arm at Week 24.Characterization of PSO skin T cells by immunophenotyping of skin cellsshowed that compared to baseline, the frequency of Treg population wasmaintained in the guselkumab arm (n=11), but was reduced in thesecukinumab arm (n=9, p<0.001) at Week 24. Statistical analysis wasperformed using SAS 9.4 software using longitudinal regression modelwith difference from lesion at baseline as response, lesion at baselineas predictor, treatment and week as factor and interaction term betweentreatment and week, and AR1 as covariance structure. Data was plotted aschange from baseline lesion using least square means and 95% confidenceinterval.

To better understand the mechanism of action of Guselkumab (GUS)(trademark name TREMFYA), we sought to characterize PsO skin T cells byflow cytometry-based immunophenotyping of cell suspensions fromdissociated biopsies. Using this approach, we showed that the relativefrequency of Treg to CD8+ tissue resident memory T cells (TRMs) in PsOskin was higher in the guselkumab cohort compared to the cohort treatedwith IL17A mAb blocker, secukinumab (COSENTYX), at week 24 (p=0.006).

TABLE 22 Summary of P values - Ratio of Tregs to CD8TRM Treatment Week Pvalues Guselkumab Week 0-NL vs Week 0-L 0.617381 Guselkumab Week 0-NL vsWeek 4 0.770112 Guselkumab Week 0-NL vs Week 24 0.085235 Guselkumab Week0-L vs Week 4 0.835498 Guselkumab Week 0-L vs Week 24 0.217772Guselkumab Week 4 vs Week 24 0.150912 Secukinumab Week 0-NL vs Week 0-L0.061484 Secukinumab Week 0-NL vs Week 4 0.594812 Secukinumab Week 0-NLvs Week 24 0.993097 Secukinumab Week 0-L vs Week 4 0.176379 SecukinumabWeek 0-L vs Week 24 0.060335 Secukinumab Week 4 vs Week 24 0.588851Guselkumab vs Secukinumab 0-NL 0.247194 Guselkumab vs Secukinumab 0-L0.729469 Guselkumab vs Secukinumab  4 0.379056 Guselkumab vs Secukinumab24 0.006053

As shown in FIG. 10 , there are a higher relative frequency ofregulatory T cells (Tregs) to CD8 tissue resident memory T cells (TRMs)in guselkumab arm compared to secukinumab arm at Week 24.Characterization of PSO skin T cells by immunophenotyping of skin cellsshowed that the ratio of Treg population to CD8 TRM population washigher in the guselkumab arm (n=11) compared to secukinumab arm (n=9,p<0.01) at Week 24. Statistical analysis was performed using SAS 9.4software using longitudinal regression model with difference from lesionat baseline as response, lesion at baseline as predictor, treatment andweek as factor and interaction term between treatment and week, and AR1as covariance structure. Data was plotted as change from baseline lesionusing least square means and 95% confidence interval.

APPENDIX

APPENDIX 1 Summary of Demographics and Baseline Characteristics; FullAnalysis Set (Study CNTO1959PSO3009) Guselkumab 100 mg Secukinumab 300mg Total Analysis set: Full analysis set 534 514 1048 Age, years N 534514 1048 Mean (SD) 46.3 (13.67)   45.3 (13.57)   45.8 (13.63)   Median  47.0   44.0    46.0 Range (18; 87)   (18; 76)   (18; 87)   IQ range(37.0; 56.0)   (35.0; 55.0)   (36.0; 55.0)   <45 years 226 (42.3%) 262(51.0%) 488 (46.6%) ≥45 to <65 years 254 (47.6%) 207 (40.3%) 461 (44.0%)≥65 years  54 (10.1%) 45 (8.8%) 99 (9.4%) Sex N 534 514 1048 Female 169(31.6%) 172 (33.5%) 341 (32.5%) Male 365 (68.4%) 342 (66.5%) 707 (67.5%)Race N 534 514 1048 American Indian or Alaska Native  2 (0.4%)  2 (0.4%) 4 (0.4%) Asian 18 (3.4%) 12 (2.3%) 30 (2.9%) Black or African American 5 (0.9%) 11 (2.1%) 16 (1.5%) Native Hawaiian or Other Pacific Islander 0     3 (0.6%)  3 (0.3%) White 499 (93.4%) 480 (93.4%) 979 (93.4%)Other  6 (1.1%)  6 (1.2%) 12 (1.1%) Multiple  4 (0.7%)  0     4 (0.4%)Ethnicity N 534 514 1048 Hispanic or Latino 27 (5.1%) 36 (7.0%) 63(6.0%) Not Hispanic or Latino 502 (94.0%) 472 (91.8%) 974 (92.9%) NotReported  5 (0.9%)  4 (0.8%)  9 (0.9%) Unknown  0     2 (0.4%)  2 (0.2%)Weight, kg N 534 512 1046 Mean (SD) 89.31 (22.953)   89.13 (20.212)  89.23 (21.645)   Median    87.60    87.00    87.00 Range (42.4;201.1)    (42.8; 177.6)    (42.4; 201.1)    IQ range (73.10; 101.30)   (75.00; 100.00)    (74.00; 100.60)    ≤90 kg 297 (55.6%) 292 (57.0%) 589(56.3%) >90 kg 237 (44.4%) 220 (43.0%) 457 (43.7%) Height, cm N 533 5111044 Mean (SD) 172.9 (10.27)   172.3 (9.63)     172.6 (9.96)     Median  173.0 172.5   172.8 Range (149; 198)   (143; 205)   (143; 205)   IQrange (166.0; 180.0)   (165.1; 179.0)   (165.2; 180.0)   Body massindex, kg/m² N 533 511 1044 Mean (SD) 29.8 (7.10)   30.0 (6.33)   29.9(6.73)   Median   28.4   29.2    28.8 Range (16; 70)   (16; 65)   (16;70)   IQ range (25.0; 33.4)   (25.5; 33.6)   (25.1; 33.6)   Normal < 25kg/m² 134 (25.1%) 109 (21.3%) 243 (23.3%) Overweight > 25 to <30 kg/m²176 (33.0%) 177 (34.6%) 353 (33.8%) Obese > 30 kg/m² 223 (41.8%) 225(44.0%) 448 (42.9%) Key: IQ = Interquartile [TSIDEM01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSIDEM01.SAS]23OCT2018, 12:56

APPENDIX 2 Summary of Psoriasis Baseline Clinical DiseaseCharacteristics; Full Analysis Set (Study CNTO1959PSO3009) Guselkumab100 mg Secukinumab 300 mg Total Analysis set: Full analysis set 534 5141048 Psoriasis disease duration (years) N 534 514 1048 Mean (SD) 18.5(12.16)   18.3 (12.67)   18.4 (12.41)   Median   17.0   15.7 16.1 Range(1; 60)    (1; 68)    (1; 68)    IQ range (9.0; 27.0)    (9.0; 25.0)   (9.0; 26.0)    Psoriasis disease duration (years) N 534 514 1048 <15years 222 (41.6%) 239 (46.5%) 461 (44.0%) ≥15 years 312 (58.4%) 275(53.5%) 587 (56.0%) Age at diagnosis (years) N 534 514 1048 Mean (SD)27.9 (14.72)   27.1 (15.05)   27.5 (14.88)   Median   26.0   25.0   25.0 Range (0; 84)    (0; 76)    (0; 84)    IQ range (16.0; 38.0)  (16.0; 37.0)   (16.0; 37.0)   Age at diagnosis (years) N 534 514 1048<25 years 253 (47.4%) 255 (49.6%) 508 (48.5%) ≥25 years 281 (52.6%) 259(50.4%) 540 (51.5%) Psoriatic arthritis N 534 514 1048 Yes  97 (18.2%) 79 (15.4%) 176 (16.8%) No 437 (81.8%) 435 (84.6%) 872 (83.2%) BSA (%) N534 514 1048 Mean (SD) 23.7 (12.85)   24.5 (14.59)   24.1 (13.73)  Median   20.0   20.0    20.0 Range (10; 86)   (10; 95)   (10; 95)   IQrange (14.0; 29.0)   (15.0; 30.0)   (15.0; 29.0)   BSA N 534 514 1048<20% 249 (46.6%) 240 (46.7%) 489 (46.7%) ≥20% 285 (53.4%) 274 (53.3%)559 (53.3%) IGA score N 534 514 1048 Cleared (0)  0     0     0   Minimal (1)  0     0     0    Mild (2)  0     1 (0.2%)  1 (0.1%)Moderate (3) 407 (76.2%) 391 (76.1%) 798 (76.1%) Severe (4) 127 (23.8%)122 (23.7%) 249 (23.8%) IGA score N 534 514 1048 <4 407 (76.2%) 392(76.3%) 799 (76.2%) =4 127 (23.8%) 122 (23.7%) 249 (23.8%) PASI score(0-72) N 534 514 1048 Mean (SD) 20.0 (7.38)   20.1 (7.63)   20.0(7.50)   Median 18.0 17.8    18.0 Range (12; 59)   (5; 65)    (5; 65)   IQ range (15.0; 22.4)   (15.2; 22.2)   (15.1; 22.3)   PASI score N 534514 1048 <20 344 (64.4%) 326 (63.4%) 670 (63.9%) ≥20 190 (35.6%) 188(36.6%) 378 (36.1%) Key: IQ = Interquartile [TSIDEM04.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSIDEM04.SAS]23OCT2018, 12:56

APPENDIX 3 Summary of Previous Psoriasis Medications and Therapies byMedication Category; Full Analysis Set (Study CNTO1959PSO3009)Guselkumab Secukinumab 100 mg 300 mg Total Analysis set: Full analysisset 534 514 1048 Topical agents N 531 514 1045 Never Used 22 (4.1%) 34(6.6%) 56 (5.4%) Ever Used 509 (95.9%) 480 (93.4%) 989 (94.6%)Phototherapy

PUVA or UVB

N 534 513 1047 Never Used 253 (47.4%) 252 (49.1%) 505 (48.2%) Ever Used281 (52.6%) 261 (50.9%) 542 (51.8%) Non-biologic systemic

PUVA, methotrexate, cyclosporine, acitretin, apremilast, or tofacitinib

N 534 514 1048 Never Used 258 (48.3%) 227 (44.2%) 485 (46.3%) ≥1 therapy276 (51.7%) 287 (55.8%) 563 (53.7%) ≥2 therapies 126 (23.6%) 132 (25.7%)258 (24.6%) ≥3 therapies 46 (8.6%) 53 (10.3%) 99 (9.4%) ≥4 therapies 10(1.9%) 4 (0.8%) 14 (1.3%) Biologics (etanercept, infliximab, alefacept,efalizumab, ustekinumab, briakinumab, ixekizumab, adalimumab,brodalumab, tildrakizuinab, or risankizuniab

N 534 514 1048 Never Used 378 (70.8%) 365 (71.0%) 743 (70.9%) Ever Used156 (29.2%) 149 (29.0%) 305 (29.1%) Non-biologic systemic or biologics N534 514 1048 Never Used 206 (38.6%) 183 (35.6%) 389 (37.1%) Ever Used328 (61.4%) 331 (64.4%) 659 (62.9%) Anti-TNFα agent (etanercept,infliximab, adalimumab

N 534 514 1048 Never Used 452 (84.6%) 429 (83.5%) 881 (84.1%) Ever Used82 (15.4%) 85 (16.5%) 167 (15.9%) IL-12/23 inhibitors (ustekinumab,briakinumab, tildrakizumab, risankizumab

N 534 514 1048 Never Used 489 (91.6%) 470 (91.4%) 959 (91.5%) Ever Used45 (8.4%) 44 (8.6%) 89 (8.5%) IL-17 inhibitors (ixekizumab, brodalumab

N 534 514 1048 Never Used 465 (87.1%) 445 (86.6%) 910 (86.8%) Ever Used69 (12.9%) 69 (13.4%) 138 (13.2%) [TSICM01A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSICM01A.SAS]23OCT2018, 12:57

APPENDIX 4 Treatment Disposition Through Week 44; Full Analysis Set(Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300 mg TotalAnalysis set: Full 534  514  1048   analysis set Discontinued study 27(5.1%)  48 (9.3%)  75 (7.2%)  treatment Reason for discontinuationAdverse event 9 (1.7%) 11 (2.1%)  20 (1.9%)  Worsening of 1 (0.2%) 1(0.2%) 2 (0.2%) Psoriasis Other Adverse 8 (1.5%) 10 (1.9%)  18 (1.7%) event Death 0 0 0 Lack of Efficacy 2 (0.4%) 7 (1.4%) 9 (0.9%) Lost toFollow-Up 2 (0.4%) 2 (0.4%) 4 (0.4%) Non-Compliance 2 (0.4%) 0 2 (0.2%)with Study Drug Product Quality 0 0 0 Complaint Study Terminated 0 0 0by Sponsor Trial Site 0 0 0 Terminated by Sponsor Withdrawal by 7 (1.3%)19 (3.7%)  26 (2.5%)  Subject Pregnancy 1 (0.2%) 1 (0.2%) 2 (0.2%)Protocol 2 (0.4%) 6 (1.2%) 8 (0.8%) Violation Other 2 (0.4%) 2 (0.4%) 4(0.4%) [TSIDS02.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSIDS02.SAS]23OCT2018, 12:56

APPENDIX 5 Summary of Exposure to Study Agent Through Week 44; SafetyAnalysis Set (Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300mg Analysis set: Safety 534  511  analysis set Total number of activeinjections received N 534  511  Mean (SD) 6.8 (0.86) 28.8 (4.18) Median  7.0   30.0 Range (1; 9) (2; 30) Total number of active injectionsreceived  1 4 (0.7%) 0  2 6 (1.1%) 2 (0.4%)  3 3 (0.6%) 0  4 3 (0.6%) 0 5 7 (1.3%) 0  6 9 (1.7%) 2 (0.4%)  7 499 (93.4%) 0  8 2 (0.4%) 1 (0.2%) 9 1 (0.2%) 0 10 0 4 (0.8%) 11 0 0 12 0 4 (0.8%) 13 0 0 14 0 4 (0.8%) 150 0 16 0 5 (1.0%) 17 0 0 18 0 6 (1.2%) 19 0 0 20 0 3 (0.6%) 21 0 0 22 03 (0.6%) 23 0 0 24 0 1 (0.2%) 25 0 0 26 0 3 (0.6%) 27 0 0 28 0 26 (5.1%)29 0 0 30 0 447 (87.5%) Total dose of study agent, mg N 534  511  Mean(SD) 682.4 (86.14) 4321.5 (627.48) Median 700.0 4500.0  Range (100; 900)(300; 4500) [TSIEX01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSIEX01.SAS]23OCT2018, 12:58Efficacy

APPENDIX 6 Number of PASI 75 Responders at Both Week 12 and Week 48(Non-Inferiority Analysis); Full Analysis Set (Study CNTO1959PSO3009)Guselkumab Secukinumab 100 mg 300 mg Analysis set: Full 534 514 analysisset PASI 75 responders 452 (84.6%) 412 (80.2%) Treatment difference 4.3%(−0.2%, 8.9%) (95% CI) p-value <0.001 Note 1: Treatment difference wascalculated adjusting for investigator site (pooled) using MH weights and95% CI was calculated adjusting for investigator site (pooled) with MHweights using Miettinen-Nurminen method. Note 2: P-value was based on1-sided MH Z-test adjusted for investigator site (pooled).[TEFPASI03A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI03A.SAS]23OCT2018, 13:06

APPENDIX 7 Number of PASI 75 Responders at Both Week 12 and Week 48(Superiority Analysis); Full Analysis Set (Study CNTO1959PSO3009)Guselkumab Secukinumab 100 mg 300 mg Analysis set: Full 534 514 analysisset PASI 75 responders 452 (84.6%) 412 (80.2%) Treatment differences4.3% (0.1%, 8.5%) (95% CI) p-value 0.062 Note 1: Treatment differenceand 95% CI were calculated adjusting for investigator site (pooled)using MH weights. Note 2: P-value was based on 1-sided CMH chi-squaretest stratified by the investigator site (pooled). [TEFPASI03B.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI03B.SAS]23OCT2018, 13:06

APPENDIX 8 Number of PASI 90 Responders at Week 12 (Non-InferiorityAnalysis); Full Analysis Set (Study CNTO1959PSO3009) GuselkumabSecukinumab 100 mg 300 mg Analysis set: Full 534 514 analysis set PASI90 responders 369 (69.1%) 391 (76.1%) Treatment difference −7.0%(−12.2%, −1.7%) (95% CI) p-value 0.127 Note 1: Treatment difference wascalculated adjusting for investigator site (pooled) using MH weights and95% CI was calculated adjusting for investigator site (pooled) with MHweights using Miettinen-Nurminen method. Note 2: P-value was based on1-sided MH Z-test adjusted for investigator site (pooled).[TEFPASI04A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI04A.SAS]23OCT2018, 13:10

APPENDIX 9 Number of PASI 75 Responders at Week 12 (Non-InferiorityAnalysis); Full Analysis Set (Study CNTO1959PSO3009) GuselkumabSecukinumab 100 mg 300 mg Analysis set: Full 534 514 analysis set PASI75 responders 477 (89.3%) 471 (91.6%) Treatment difference −2.3% (−6.0%,1.2%) (95% CI) p-value <0.001 Note 1: Treatment difference wascalculated adjusting for investigator site (pooled) using MH weights and95% CI was calculated adjusting for investigator site (pooled) with MHweights using Miettinen-Nurminen method. Note 2: P-value was based on1-sided MH Z-test adjusted for investigator site (pooled).[TEFPASI05A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI05A.SAS]23OCT2018, 13:13

APPENDIX 10 Number of PASI 100 Responders at Week 48 (SuperiorityAnalysis); Full Analysis Set (Study CNTO1959PSO3009) GuselkumabSecukinumab 100 mg 300 mg Analysis set: Full 534 514 analysis set PASI100 responders 311 (58.2%) 249 (48.4%) Treatment differences 9.7% (4.2%,15.1%) (95% CI) p-value 0.001 Note 1: Treatment difference and 95% CIwere calculated adjusting for investigator site (pooled) using MHweights. Note 2: P-value was based on CMH chi-square test stratified bythe investigator site (pooled). [TEFPASI06B.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI06B.SAS]23OCT2018, 13:17

APPENDIX 11 Number of Subjects With IGA Score of Cleared (0) at Week 48(Superiority Analysis); Full Analysis Set (Study CNTO1959PSO3009)Guselkumab Secukinumab 100 mg 300 mg Analysis set: Full 534 514 analysisset Subjects with IGA 332 (62.2%) 259 (50.4%) score of cleared (0)Treatment difference 11.6% (6.2%, 17.1%) (95% CI) p-value <0.001 Note 1:Treatment difference and 95% CI were calculated adjusting forinvestigator site (pooled) using MH weights. Note 2: P-value was basedon CMH chi-square test stratified by the investigator site (pooled).[TEFIGA01B.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFIGA01B.SAS]23OCT2018, 13:20

APPENDIX 12 Number of Subjects With IGA Score of Cleared (0) or Minimal(1) at Week 48 (Superiority Analysis); Full Analysis Set (StudyCNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300 mg Analysis set: Full534 514 analysis set Subjects with IGA 454 (85.0%) 385 (74.9%) score ofcleared (0) or minimal (1) Treatment difference 9.7% (5.3%, 14.0%) (95%CI) p-value <0.001 Note 1: Treatment difference and 95% CI werecalculated adjusting for investigator site (pooled) using MH weights.Note 2: P-value was based on CMH chi-square test stratified by theinvestigator site (pooled). [TEFIGA02B.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFIGA02B.SAS]23OCT2018, 13:24

APPENDIX 13 Number of Subjects Achieving a PASI 90 Response at All 7Visits From Week 24 Through Week 48 (Superiority Analysis); FullAnalysis Set (Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300mg Analysis set: Full 534 514 analysis set PASI 90 responders 379(71.0%) 316 (61.5%) Treatment difference 9.8% (4.6%, 14.9%) (95% CI)p-value <0.001 Note 1: Treatment difference and 95% CI were calculatedadjusting for investigator site (pooled) using MH weights. Note 2:P-value was based on CMH chi-square test stratified by the investigatorsite (pooled). [TEFPASI10B.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI10B.SAS]23OCT2018, 13:28

APPENDIX 14 Summary of PASI Responses Through Week 56 by Visit; FullAnalysis Set (Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300mg Analysis set: Full 534 514 analysis set Week 1 N 534 514 100%improvement  0  0 ≥90% improvement  0  0 ≥75% improvement 11 (2.1%) 9(1.8%) ≥50% improvement 57 (10.7%) 66 (12.8%) Week 2 N 534 514 100%improvement 1 (0.2%) 3 (0.6%) ≥90% improvement 6 (1.1%) 14 (2.7%) ≥75%improvement 34 (6.4%) 59 (11.5%) ≥50% improvement 165 (30.9%) 216(42.0%) Week 3 N 534 514 100% improvement 9 (1.7%) 8 (1.6%) ≥90%improvement 30 (5.6%) 44 (8.6%) ≥75% improvement 104 (19.5%) 146 (28.4%)≥50% improvement 301 (56.4%) 344 (66.9%) Week 4 N 534 514 100%improvement 22 (4.1%) 26 (5.1%) ≥90% improvement 70 (13.1%) 112 (21.8%)≥75% improvement 210 (39.3%) 258 (50.2%) ≥50% improvement 392 (73.4%)439 (85.4%) Week 8 N 534 514 100% improvement 107 (20.0%) 140 (27.2%)≥90% improvement 260 (48.7%) 319 (62.1%) ≥75% improvement 408 (76.4%)443 (86.2%) ≥50% improvement 509 (95.3%) 498 (96.9%) Week 12 N 534 514100% improvement 202 (37.8%) 216 (42.0%) ≥90% improvement 369 (69.1%)391 (76.1%) ≥75% improvement 477 (89.3%) 471 (91.6%) ≥50% improvement517 (96.8%) 494 (96.1%) Week 16 N 534 514 100% improvement 255 (47.8%)237 (46.1%) ≥90% improvement 419 (78.5%) 409 (79.6%) ≥75% improvement495 (92.7%) 477 (92.8%) ≥50% improvement 521 (97.6%) 495 (96.3%) Week 20N 534 514 100% improvement 274 (51.3%) 250 (48.6%) ≥90% improvement 428(80.1%) 417 (81.1%) ≥75% improvement 500 (93.6%) 475 (92.4%) ≥50%improvement 521 (97.6%) 489 (95.1%) Week 24 N 534 514 100% improvement292 (54.7%) 259 (50.4%) ≥90% improvement 444 (83.1%) 402 (78.2%) ≥75%improvement 503 (94.2%) 464 (90.3%) ≥50% improvement 522 (97.8%) 478(93.0%) Week 28 N 534 514 100% improvement 305 (57.1%) 262 (51.0%) ≥90%improvement 456 (85.4%) 397 (77.2%) ≥75% improvement 502 (94.0%) 464(90.3%) ≥50% improvement 519 (97.2%) 478 (93.0%) Week 32 N 534 514 100%improvement 307 (57.5%) 258 (50.2%) ≥90% improvement 453 (84.8%) 398(77.4%) ≥75% improvement 502 (94.0%) 459 (89.3%) ≥50% improvement 518(97.0%) 478 (93.0%) Week 36 N 534 514 100% improvement 313 (58.6%) 257(50.0%) ≥90% improvement 451 (84.5%) 389 (75.7%) ≥75% improvement 500(93.6%) 447 (87.0%) ≥50% improvement 519 (97.2%) 474 (92.2%) Week 40 N534 514 100% improvement 311 (58.2%) 250 (48.6%) ≥90% improvement 452(84.6%) 379 (73.7%) ≥75% improvement 496 (92.9%) 441 (85.8%) ≥50%improvement 512 (95.9%) 467 (90.9%) Week 44 N 534 514 100% improvement313 (58.6%) 254 (49.4%) ≥90% improvement 449 (84.1%) 373 (72.6%) ≥75%improvement 493 (92.3%) 438 (85.2%) ≥50% improvement 503 (94.2%) 470(91.4%) Week 48 N 534 514 100% improvement 311 (58.2%) 249 (48.4%) ≥90%improvement 451 (84.5%) 360 (70.0%) ≥75% improvement 492 (92.1%) 429(83.5%) ≥50% improvement 502 (94.0%) 459 (89.3%) Week 56 N 534 514 100%improvement 269 (50.4%) 139 (27.0%) ≥90% improvement 413 (77.3%) 264(51.4%) ≥75% improvement 470 (88.0%) 362 (70.4%) ≥50% improvement 486(91.0%) 422 (82.1%) [TEFPASI13A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFPASI13A.SAS]23OCT2018, 13:29

APPENDIX 15 Summary of IGA Responses Through Week 56 by Visit; FullAnalysis Set (Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300mg Analysis set: Full analysis set 534 514 Week 1 N 534 514 IGA ofcleared (0)  0  0 IGA of cleared (0) or minimal (1) 18 (3.4%) 13 (2.5%)IGA of mild or better (≤2) 145 (27.2%) 176 (34.2%) Week 2 N 534 514 IGAof cleared (0) 1 (0.2%) 4 (0.8%) IGA of cleared (0) or minimal (1) 66(12.4%) 104 (20.2%) IGA of mild or better (≤2) 289 (54.1%) 328 (63.8%)Week 3 N 534 514 IGA of cleared (0) 14 (2.6%) 17 (3.3%) IGA of cleared(0) or minimal (1) 145 (27.2%) 205 (39.9%) IGA of mild or better (≤2)402 (75.3%) 424 (82.5%) Week 4 N 534 514 IGA of cleared (0) 36 (6.7%) 50(9.7%) IGA of cleared (0) or minimal (1) 236 (44.2%) 305 (59.3%) IGA ofmild or better (≤2) 457 (85.6%) 474 (92.2%) Week 8 N 534 514 IGA ofcleared (0) 156 (29.2%) 184 (35.8%) IGA of cleared (0) or minimal (1)409 (76.6%) 429 (83.5%) IGA of mild or better (≤2) 514 (96.3%) 495(96.3%) Week 12 N 534 514 IGA of cleared (0) 247 (46.3%) 258 (50.2%) IGAof cleared (0) or minimal (1) 457 (85.6%) 444 (86.4%) IGA of mild orbetter (≤2) 517 (96.8%) 490 (95.3%) Week 16 N 534 514 IGA of cleared (0)296 (55.4%) 275 (53.5%) IGA of cleared (0) or minimal (1) 463 (86.7%)445 (86.6%) IGA of mild or better (≤2) 517 (96.8%) 487 (94.7%) Week 20 N534 514 IGA of cleared (0) 304 (56.9%) 277 (53.9%) IGA of cleared (0) orminimal (1) 469 (87.8%) 440 (85.6%) IGA of mild or better (≤2) 509(95.3%) 479 (93.2%) Week 24 N 534 514 IGA of cleared (0) 326 (61.0%) 288(56.0%) IGA of cleared (0) or minimal (1) 473 (88.6%) 425 (82.7%) IGA ofmild or better (≤2) 514 (96.3%) 471 (91.6%) Week 28 N 534 514 IGA ofcleared (0) 332 (62.2%) 289 (56.2%) IGA of cleared (0) or minimal (1)469 (87.8%) 426 (82.9%) IGA of mild or better (≤2) 510 (95.5%) 467(90.9%) Week 32 N 534 514 IGA of cleared (0) 337 (63.1%) 280 (54.5%) IGAof cleared (0) or minimal (1) 473 (88.6%) 419 (81.5%) IGA of mild orbetter (≤2) 510 (95.5%) 465 (90.5%) Week 36 N 534 514 IGA of cleared (0)324 (60.7%) 276 (53.7%) IGA of cleared (0) or minimal (1) 462 (86.5%)409 (79.6%) IGA of mild or better (≤2) 510 (95.5%) 457 (88.9%) Week 40 N534 514 IGA of cleared (0) 337 (63.1%) 269 (52.3%) IGA of cleared (0) orminimal (1) 461 (86.3%) 401 (78.0%) IGA of mild or better (≤2) 500(93.6%) 452 (87.9%) Week 44 N 534 514 IGA of cleared (0) 332 (62.2%) 267(51.9%) IGA of cleared (0) or minimal (1) 459 (86.0%) 393 (76.5%) IGA ofmild or better (≤2) 493 (92.3%) 450 (87.5%) Week 48 N 534 514 IGA ofcleared (0) 332 (62.2%) 259 (50.4%) IGA of cleared (0) or minimal (1)454 (85.0%) 385 (74.9%) IGA of mild or better (≤2) 495 (92.7%) 446(86.8%) Week 56 N 534 514 IGA of cleared (0) 290 (54.3%) 151 (29.4%) IGAof cleared (0) or minimal (1) 421 (78.8%) 299 (58.2%) IGA of mild orbetter (≤2) 467 (87.5%) 392 (76.3%) [TEFIGA05A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TEFIGA05A.SAS]23OCT2018,13:28Safety

APPENDIX 16 Number of Subjects With Treatment-Emergent Adverse EventsThrough Week 56 by System Organ Class and Preferred Term; SafetyAnalysis Set (Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300mg Analysis set: Safety analysis set 534  511  Avg duration of follow-up(weeks)  54.90  53.67 Avg exposure (number of  14.65  14.41administrations) Subjects with 1 or more AEs 416 (77.9%) 417 (81.6%)System organ class Preferred term Infections and infestations 310(58.1%) 324 (63.4%) Nasopharyngitis 118 (22.1%) 125 (24.5%) Upperrespiratory tract infection 83 (15.5%) 92 (18.0%) Pharyngitis 24 (4.5%)22 (4.3%) Influenza 20 (3.7%) 13 (2.5%) Bronchitis 17 (3.2%) 15 (2.9%)Oral herpes 11 (2.1%) 14 (2.7%) Urinary tract infection 11 (2.1%) 11(2.2%) Gastroenteritis 10 (1.9%) 9 (1.8%) Sinusitis 10 (1.9%) 12 (2.3%)Gastroenteritis viral 9 (1.7%) 8 (1.6%) Rhinitis 9 (1.7%) 13 (2.5%)Viral upper respiratory tract 9 (1.7%) 8 (1.6%) infection Folliculitis 8(1.5%) 10 (2.0%) Tonsillitis 7 (1.3%) 15 (2.9%) Tinea pedis 6 (1.1%) 16(3.1%) Gastrointestinal infection 5 (0.9%) 0 Oral candidiasis 5 (0.9%)11 (2.2%) Tooth abscess 5 (0.9%) 3 (0.6%) Tooth infection 5 (0.9%) 2(0.4%) Vulvovaginal candidiasis 5 (0.9%) 13 (2.5%) Acute sinusitis 4(0.7%) 0 Cellulitis 4 (0.7%) 3 (0.6%) Conjunctivitis 4 (0.7%) 17 (3.3%)Respiratory tract infection 4 (0.7%) 2 (0.4%) Tinea versicolour 4 (0.7%)5 (1.0%) Gastrointestinal viral infection 3 (0.6%) 1 (0.2%)Periodontitis 3 (0.6%) 5 (1.0%) Pneumonia 3 (0.6%) 6 (1.2%) Cystitis 2(0.4%) 2 (0.4%) Ear infection 2 (0.4%) 5 (1.0%) Helicobacter 2 (0.4%) 0gastritis Hordeolum 2 (0.4%) 8 (1.6%) Laryngitis 2 (0.4%) 2 (0.4%)Localised infection 2 (0.4%) 1 (0.2%) Otitis media 2 (0.4%) 6 (1.2%)Postoperative wound infection 2 (0.4%) 0 Skin Candida 2 (0.4%) 3 (0.6%)Tinea cruris 2 (0.4%) 4 (0.8%) Wound infection 2 (0.4%) 1 (0.2%)Acarodermatitis 1 (0.2%) 2 (0.4%) Anal abscess 1 (0.2%) 0 Anal fistulainfection 1 (0.2%) 0 Appendicitis 1 (0.2%) 0 Arthritis infective 1(0.2%) 0 Bacterial rhinitis 1 (0.2%) 0 Bacterial vulvovaginitis 1 (0.2%)0 Candida infection 1 (0.2%) 0 Conjunctivitis bacterial 1 (0.2%) 0Dermatitis infected 1 (0.2%) 2 (0.4%) Dermo-hypodermitis 1 (0.2%) 0Diverticulitis 1 (0.2%) 3 (0.6%) Enterobiasis 1 (0.2%) 0 Erysipelas 1(0.2%) 0 Fungal skin infection 1 (0.2%) 0 Furuncle 1 (0.2%) 2 (0.4%)Gangrene 1 (0.2%) 0 Gastroenteritis yersinia 1 (0.2%) 0 Genital herpes 1(0.2%) 3 (0.6%) Gingivitis 1 (0.2%) 2 (0.4%) Impetigo 1 (0.2%) 4 (0.8%)Labyrinthitis 1 (0.2%) 0 Mastitis 1 (0.2%) 0 Nasal herpes 1 (0.2%) 1(0.2%) Ophthalmic herpes zoster 1 (0.2%) 0 Paronychia 1 (0.2%) 2 (0.4%)Peritonsillar abscess 1 (0.2%) 0 Pilonidal cyst 1 (0.2%) 0 Pyoderma 1(0.2%) 0 Salmonellosis 1 (0.2%) 0 Sepsis 1 (0.2%) 0 Skin bacterialinfection 1 (0.2%) 0 Upper respiratory tract infection 1 (0.2%) 0bacterial Urinary tract infection bacterial 1 (0.2%) 0 Viral pharyngitis1 (0.2%) 0 Abscess 0 1 (0.2%) Abscess limb 0 1 (0.2%) Angular cheilitis0 3 (0.6%) Application site cellulitis 0 1 (0.2%) Bacterial vaginosis 01 (0.2%) Balanitis Candida 0 2 (0.4%) Blister infected 0 1 (0.2%) Bodytinea 0 2 (0.4%) Bullous impetigo 0 1 (0.2%) Dermatophytosis 0 1 (0.2%)Eczema impetiginous 0 1 (0.2%) Eczema infected 0 2 (0.4%) Groin abscess0 1 (0.2%) Helicobacter infection 0 1 (0.2%) Herpes simplex 0 1 (0.2%)Herpes zoster 0 4 (0.8%) Neuroborreliosis 0 1 (0.2%) Onychomycosis 0 1(0.2%) Otitis externa 0 3 (0.6%) Otitis media acute 0 1 (0.2%) Perianalstreptococcal infection 0 1 (0.2%) Peritonsillitis 0 1 (0.2%)Pharyngitis streptococcal 0 4 (0.8%) Pharyngotonsillitis 0 1 (0.2%)Pulpitis dental 0 2 (0.4%) Pyelonephritis 0 1 (0.2%) Respiratorysyncytial virus 0 1 (0.2%) infection Respiratory tract infection viral 01 (0.2%) Sialoadenitis 0 1 (0.2%) Soft tissue infection 0 1 (0.2%)Staphylococcal skin infection 0 3 (0.6%) Subcutaneous abscess 0 2 (0.4%)Tracheobronchitis 0 1 (0.2%) Vaginal infection 0 2 (0.4%) Vulvovaginalmycotic infection 0 2 (0.4%) Musculoskeletal and connective 98 (18.4%)93 (18.2%) tissue disorders Arthralgia 30 (5.6%) 25 (4.9%) Back pain 29(5.4%) 18 (3.5%) Myalgia 11 (2.1%) 7 (1.4%) Musculoskeletal pain 7(1.3%) 7 (1.4%) Psoriatic arthropathy 7 (1.3%) 3 (0.6%) Osteoarthritis 6(1.1%) 4 (0.8%) Joint swelling 5 (0.9%) 3 (0.6%) Tendonitis 5 (0.9%) 2(0.4%) Muscle spasms 4 (0.7%) 5 (1.0%) Neck pain 4 (0.7%) 5 (1.0%) Jointeffusion 3 (0.6%) 1 (0.2%) Pain in extremity 3 (0.6%) 6 (1.2%)Musculoskeletal chest pain 2 (0.4%) 2 (0.4%) Plantar fasciitis 2 (0.4%)0 Spinal pain 2 (0.4%) 3 (0.6%) Arthritis 1 (0.2%) 1 (0.2%) Chondropathy1 (0.2%) 0 Enthesopathy 1 (0.2%) 0 Exostosis 1 (0.2%) 0 Fibromyalgia 1(0.2%) 0 Groin pain 1 (0.2%) 1 (0.2%) Intervertebral disc degeneration 1(0.2%) 0 Joint stiffness 1 (0.2%) 1 (0.2%) Muscle tightness 1 (0.2%) 0Myofascial pain syndrome 1 (0.2%) 0 Rotator cuff syndrome 1 (0.2%) 2(0.4%) Spinal osteoarthritis 1 (0.2%) 3 (0.6%) Synovial cyst 1 (0.2%) 0Synovitis 1 (0.2%) 0 Trigger finger 1 (0.2%) 0 Bursitis 0 3 (0.6%)Costochondritis 0 1 (0.2%) Flank pain 0 1 (0.2%) Intervertebral discdisorder 0 3 (0.6%) Intervertebral disc protrusion 0 2 (0.4%)Musculoskeletal stiffness 0 1 (0.2%) Osteopenia 0 1 (0.2%) Periarthritis0 1 (0.2%) Sacroiliitis 0 1 (0.2%) Spinal column stenosis 0 1 (0.2%)Spondylolisthesis 0 1 (0.2%) Temporomandibular joint syndrome 0 1 (0.2%)Tenosynovitis stenosans 0 1 (0.2%) Nervous system disorders 79 (14.8%)71 (13.9%) Headache 49 (9.2%) 48 (9.4%) Sciatica 8 (1.5%) 6 (1.2%)Migraine 6 (1.1%) 4 (0.8%) Hypoaesthesia 3 (0.6%) 2 (0.4%) Paraesthesia3 (0.6%) 0 Presyncope 2 (0.4%) 1 (0.2%) Aphonia 1 (0.2%) 0 Burningsensation 1 (0.2%) 0 Carpal tunnel syndrome 1 (0.2%) 2 (0.4%)Cervicobrachial syndrome 1 (0.2%) 0 Cluster headache 1 (0.2%) 0Disturbance in attention 1 (0.2%) 0 Dizziness postural 1 (0.2%) 0Dysaesthesia 1 (0.2%) 1 (0.2%) Facial neuralgia 1 (0.2%) 0Hyperaesthesia 1 (0.2%) 0 Memory impairment 1 (0.2%) 0 Nerve compression1 (0.2%) 0 Piriformis syndrome 1 (0.2%) 0 Spinal cord infarction 1(0.2%) 0 Spinal meningeal cyst 1 (0.2%) 0 Syncope 1 (0.2%) 4 (0.8%)Tension headache 1 (0.2%) 0 Tremor 1 (0.2%) 0 Vertebral artery stenosis1 (0.2%) 0 White matter lesion 1 (0.2%) 0 Cerebral cyst 0 1 (0.2%)Cerebrovascular accident 0 1 (0.2%) Dizziness 0 5 (1.0%) Dysgeusia 0 1(0.2%) Facial paralysis 0 1 (0.2%) Head discomfort 0 1 (0.2%) Lethargy 01 (0.2%) Neuralgia 0 3 (0.6%) Neuropathy peripheral 0 1 (0.2%) Postherpetic neuralgia 0 1 (0.2%) Post-traumatic headache 0 1 (0.2%)Gastrointestinal disorders 78 (14.6%) 77 (15.1%) Diarrhoea 27 (5.1%) 20(3.9%) Abdominal pain upper 10 (1.9%) 7 (1.4%) Gastrooesophageal refluxdisease 7 (1.3%) 8 (1.6%) Abdominal pain 6 (1.1%) 7 (1.4%) Nausea 6(1.1%) 8 (1.6%) Vomiting 6 (1.1%) 2 (0.4%) Toothache 5 (0.9%) 4 (0.8%)Constipation 3 (0.6%) 4 (0.8%) Enteritis 3 (0.6%) 0 Flatulence 3 (0.6%)1 (0.2%) Gastritis 3 (0.6%) 2 (0.4%) Dental caries 2 (0.4%) 0 Frequentbowel movements 2 (0.4%) 1 (0.2%) Umbilical hernia 2 (0.4%) 1 (0.2%)Abdominal discomfort 1 (0.2%) 1 (0.2%) Abdominal distension 1 (0.2%) 0Abdominal pain lower 1 (0.2%) 0 Anal fissure 1 (0.2%) 0 Anal fistula 1(0.2%) 0 Colitis microscopic 1 (0.2%) 0 Diverticulum intestinal 1 (0.2%)0 Dry mouth 1 (0.2%) 0 Dyspepsia 1 (0.2%) 2 (0.4%) Glossitis 1 (0.2%) 0Haematochezia 1 (0.2%) 1 (0.2%) Haemorrhoidal haemorrhage 1 (0.2%) 0Haemorrhoids 1 (0.2%) 2 (0.4%) Hyperchlorhydria 1 (0.2%) 0 Inguinalhernia 1 (0.2%) 0 Irritable bowel syndrome 1 (0.2%) 1 (0.2%) Largeintestine polyp 1 (0.2%) 1 (0.2%) Leukoplakia oral 1 (0.2%) 0 Mucousstools 1 (0.2%) 0 Palatal oedema 1 (0.2%) 0 Rectal polyp 1 (0.2%) 0Abdominal hernia 0 1 (0.2%) Anal pruritus 0 1 (0.2%) Aphthous ulcer 0 8(1.6%) Apical granuloma 0 1 (0.2%) Burning mouth syndrome 0 1 (0.2%)Chronic gastritis 0 1 (0.2%) Colitis 0 1 (0.2%) Crohn's disease 0 1(0.2%) Dysphagia 0 3 (0.6%) Food poisoning 0 2 (0.4%) Functionalgastrointestinal 0 1 (0.2%) disorder Gingival bleeding 0 1 (0.2%)Gingival recession 0 1 (0.2%) Hiatus hernia 0 1 (0.2%) Inflammatorybowel disease 0 2 (0.4%) Odynophagia 0 2 (0.4%) Tooth impacted 0 1(0.2%) Skin and subcutaneous tissue 76 (14.2%) 92 (18.0%) disordersPruritus 17 (3.2%) 12 (2.3%) Acne 4 (0.7%) 3 (0.6%) Dermatitis 4 (0.7%)7 (1.4%) Dermatitis contact 4 (0.7%) 8 (1.6%) Eczema 4 (0.7%) 7 (1.4%)Psoriasis 4 (0.7%) 11 (2.2%) Skin lesion 3 (0.6%) 2 (0.4%) Urticaria 3(0.6%) 9 (1.8%) Actinic keratosis 2 (0.4%) 2 (0.4%) Alopecia 2 (0.4%) 4(0.8%) Blister 2 (0.4%) 0 Chronic cutaneous lupus 2 (0.4%) 0erythematosus Drug eruption 2 (0.4%) 1 (0.2%) Dry skin 2 (0.4%) 3 (0.6%)Eczema asteatotic 2 (0.4%) 2 (0.4%) Hyperkeratosis 2 (0.4%) 0 Papule 2(0.4%) 1 (0.2%) Photosensitivity reaction 2 (0.4%) 0 Polymorphic lighteruption 2 (0.4%) 0 Pruritus generalised 2 (0.4%) 2 (0.4%) Rash 2 (0.4%)1 (0.2%) Angioedema 1 (0.2%) 0 Cafe au lait spots 1 (0.2%) 2 (0.4%)Dermal cyst 1 (0.2%) 3 (0.6%) Dermatitis atopic 1 (0.2%) 1 (0.2%)Erythema 1 (0.2%) 2 (0.4%) Ingrowing nail 1 (0.2%) 0 Ingrown hair 1(0.2%) 0 Intertrigo 1 (0.2%) 8 (1.6%) Lentigo 1 (0.2%) 0 Milia 1 (0.2%)0 Miliaria 1 (0.2%) 1 (0.2%) Night sweats 1 (0.2%) 1 (0.2%) Onycholysis1 (0.2%) 1 (0.2%) Perioral dermatitis 1 (0.2%) 0 Pityriasis 1 (0.2%) 0Pityriasis rosea 1 (0.2%) 0 Rash morbilliform 1 (0.2%) 0 Rash papular 1(0.2%) 2 (0.4%) Rosacea 1 (0.2%) 0 Seborrhoeic dermatitis 1 (0.2%) 8(1.6%) Skin burning sensation 1 (0.2%) 0 Skin exfoliation 1 (0.2%) 0Skin ulcer 1 (0.2%) 1 (0.2%) Solar dermatitis 1 (0.2%) 0 Alopeciascarring 0 1 (0.2%) Dermatitis allergic 0 1 (0.2%) Diffuse alopecia 0 1(0.2%) Dyshidrotic eczema 0 2 (0.4%) Eczema nummular 0 1 (0.2%)Ephelides 0 1 (0.2%) Hair growth rate abnormal 0 1 (0.2%) Handdermatitis 0 1 (0.2%) Hyperhidrosis 0 1 (0.2%) Idiopathic urticaria 0 1(0.2%) Keratolysis exfoliativa acquired 0 1 (0.2%) Keratosis pilaris 0 1(0.2%) Myxoid cyst 0 1 (0.2%) Neurodermatitis 0 3 (0.6%) Photodermatosis0 1 (0.2%) Pruritus allergic 0 1 (0.2%) Rash maculo-papular 0 1 (0.2%)Skin fissures 0 3 (0.6%) Skin texture abnormal 0 1 (0.2%) Stasisdermatitis 0 1 (0.2%) Urticaria pressure 0 1 (0.2%) Respiratory,thoracic and 59 (11.0%) 59 (11.5%) mediastinal disorders Cough 20 (3.7%)21 (4.1%) Oropharyngeal pain 12 (2.2%) 11 (2.2%) Nasal congestion 7(1.3%) 6 (1.2%) Rhinorrhoea 6 (1.1%) 9 (1.8%) Rhinitis allergic 4 (0.7%)0 Sinus congestion 4 (0.7%) 3 (0.6%) Dysphonia 2 (0.4%) 0 Dyspnoea 2(0.4%) 2 (0.4%) Productive cough 2 (0.4%) 1 (0.2%) Asthma 1 (0.2%) 3(0.6%) Catarrh 1 (0.2%) 0 Dry throat 1 (0.2%) 0 Dyspnoea exertional 1(0.2%) 0 Epistaxis 1 (0.2%) 0 Interstitial lung disease 1 (0.2%) 0 Nasalcyst 1 (0.2%) 0 Nasal polyps 1 (0.2%) 0 Oropharyngeal discomfort 1(0.2%) 0 Pneumonia aspiration 1 (0.2%) 0 Respiratory disorder 1 (0.2%) 0Sneezing 1 (0.2%) 0 Upper respiratory tract congestion 1 (0.2%) 0Adenoidal hypertrophy 0 1 (0.2%) Asthmatic crisis 0 1 (0.2%) Bronchialhyperreactivity 0 1 (0.2%) Chronic obstructive pulmonary 0 1 (0.2%)disease Lower respiratory tract congestion 0 1 (0.2%) Nasal ulcer 0 1(0.2%) Pulmonary embolism 0 1 (0.2%) Sleep apnoea syndrome 0 1 (0.2%)Throat irritation 0 2 (0.4%) General disorders and 56 (10.5%) 58 (11.4%)administration site conditions Fatigue 10 (1.9%) 7 (1.4%) Injection siteerythema 10 (1.9%) 7 (1.4%) Injection site haematoma 6 (1.1%) 5 (1.0%)Injection site pain 6 (1.1%) 7 (1.4%) Injection site pruritus 5 (0.9%) 0Non-cardiac chest pain 5 (0.9%) 6 (1.2%) Pyrexia 5 (0.9%) 6 (1.2%)Oedema peripheral 4 (0.7%) 4 (0.8%) Influenza like illness 3 (0.6%) 5(1.0%) Injection site bruising 3 (0.6%) 2 (0.4%) Injection site swelling3 (0.6%) 1 (0.2%) Adverse drug reaction 2 (0.4%) 0 Asthenia 2 (0.4%) 2(0.4%) Cyst 2 (0.4%) 1 (0.2%) Injection site induration 2 (0.4%) 0Calcinosis 1 (0.2%) 0 Chest pain 1 (0.2%) 1 (0.2%) Face oedema 1 (0.2%)0 General physical health 1 (0.2%) 0 deterioration Generalised oedema 1(0.2%) 0 Hernia pain 1 (0.2%) 0 Injection site extravasation 1 (0.2%) 0Injection site haemorrhage 1 (0.2%) 2 (0.4%) Injection site oedema 1(0.2%) 2 (0.4%) Injection site rash 1 (0.2%) 0 Malaise 1 (0.2%) 0 Pain 1(0.2%) 0 Tenderness 1 (0.2%) 0 Xerosis 1 (0.2%) 2 (0.4%) Axillary pain 01 (0.2%) Chest discomfort 0 1 (0.2%) Discomfort 0 2 (0.4%) Exercisetolerance decreased 0 1 (0.2%) Feeling cold 0 2 (0.4%) Injection siteinflammation 0 1 (0.2%) Injury associated with device 0 1 (0.2%) Nodule0 1 (0.2%) Swelling 0 1 (0.2%) Vessel puncture site haemorrhage 0 1(0.2%) Injury, poisoning and procedural 56 (10.5%) 54 (10.6%)complications Laceration 7 (1.3%) 6 (1.2%) Ligament sprain 5 (0.9%) 4(0.8%) Procedural pain 4 (0.7%) 1 (0.2%) Arthropod sting 3 (0.6%) 0Contusion 3 (0.6%) 8 (1.6%) Limb injury 3 (0.6%) 1 (0.2%) Arthropod bite2 (0.4%) 1 (0.2%) Hand fracture 2 (0.4%) 1 (0.2%) Joint dislocation 2(0.4%) 0 Ligament rupture 2 (0.4%) 1 (0.2%) Meniscus injury 2 (0.4%) 1(0.2%) Muscle strain 2 (0.4%) 6 (1.2%) Rib fracture 2 (0.4%) 2 (0.4%)Tooth fracture 2 (0.4%) 1 (0.2%) Tooth injury 2 (0.4%) 0 Wound 2 (0.4%)0 Animal scratch 1 (0.2%) 0 Arterial injury 1 (0.2%) 0 Chest injury 1(0.2%) 0 Clavicle fracture 1 (0.2%) 0 Concussion 1 (0.2%) 0Craniocerebral injury 1 (0.2%) 1 (0.2%) Electrical burn 1 (0.2%) 0 Footfracture 1 (0.2%) 1 (0.2%) Foreign body in eye 1 (0.2%) 0 Joint injury 1(0.2%) 1 (0.2%) Overdose 1 (0.2%) 0 Procedural hypertension 1 (0.2%) 0Radius fracture 1 (0.2%) 1 (0.2%) Skin abrasion 1 (0.2%) 5 (1.0%) Skullfracture 1 (0.2%) 0 Spinal column injury 1 (0.2%) 0 Thermal burn 1(0.2%) 4 (0.8%) Venomous sting 1 (0.2%) 0 Bone contusion 0 2 (0.4%)Dental restoration failure 0 1 (0.2%) Ear abrasion 0 1 (0.2%)Epicondylitis 0 3 (0.6%) Eye contusion 0 1 (0.2%) Femoral neck fracture0 1 (0.2%) Palate injury 0 1 (0.2%) Post procedural diarrhoea 0 1 (0.2%)Post-traumatic neck syndrome 0 1 (0.2%) Soft tissue injury 0 2 (0.4%)Tendon rupture 0 2 (0.4%) Upper limb fracture 0 1 (0.2%) Wrist fracture0 1 (0.2%) Investigations 37 (6.9%) 32 (6.3%) Alanine aminotransferase15 (2.8%) 10 (2.0%) increased Aspartate aminotransferase 10 (1.9%) 6(1.2%) increased Blood pressure increased 6 (1.1%) 4 (0.8%) Bloodbilirubin increased 3 (0.6%) 0 Blood glucose increased 2 (0.4%) 1 (0.2%)Electrocardiogram T wave 2 (0.4%) 0 amplitude decreased Faecalcalprotectin increased 2 (0.4%) 0 Hepatic enzyme increased 2 (0.4%) 3(0.6%) Transaminases increased 2 (0.4%) 2 (0.4%) Blood iron decreased 1(0.2%) 0 C-reactive protein increased 1 (0.2%) 0 Electrocardiogram Twave inversion 1 (0.2%) 0 Electrocardiogram repolarisation 1 (0.2%) 0abnormality Liver function test increased 1 (0.2%) 0 Serum ferritindecreased 1 (0.2%) 0 Weight increased 1 (0.2%) 1 (0.2%) Blood alkalinephosphatase 0 2 (0.4%) increased Blood creatine phosphokinase 0 1 (0.2%)increased Blood creatinine increased 0 1 (0.2%) Blood pressure systolicincreased 0 1 (0.2%) Blood triglycerides increased 0 1 (0.2%)Computerised tomogram coronary 0 1 (0.2%) artery abnormal Ejectionfraction abnormal 0 1 (0.2%) Neutrophil count decreased 0 2 (0.4%)Occult blood 0 1 (0.2%) Platelet count decreased 0 1 (0.2%) Ultrasoundliver abnormal 0 1 (0.2%) Weight decreased 0 2 (0.4%) White blood cellcount decreased 0 1 (0.2%) Vascular disorders 33 (6.2%) 33 (6.5%)Hypertension 22 (4.1%) 22 (4.3%) Hypertensive crisis 2 (0.4%) 0Peripheral arterial occlusive 2 (0.4%) 0 disease Aortic aneurysm 1(0.2%) 0 Arteriosclerosis 1 (0.2%) 0 Haematoma 1 (0.2%) 1 (0.2%) Hotflush 1 (0.2%) 2 (0.4%) Hypotension 1 (0.2%) 2 (0.4%) Varicose vein 1(0.2%) 0 Vein rupture 1 (0.2%) 0 Deep vein thrombosis 0 1 (0.2%)Diastolic hypertension 0 1 (0.2%) Flushing 0 1 (0.2%) Lymphoedema 0 1(0.2%) Orthostatic hypotension 0 1 (0.2%) Peripheral vascular disorder 01 (0.2%) Phlebitis superficial 0 1 (0.2%) Neoplasms benign, malignantand 24 (4.5%) 19 (3.7%) unspecified (incl cysts and polyps) Skinpapilloma 6 (1.1%) 3 (0.6%) Melanocytic naevus 5 (0.9%) 4 (0.8%) Basalcell carcinoma 3 (0.6%) 2 (0.4%) Squamous cell carcinoma of skin 2(0.4%) 0 Acrochordon 1 (0.2%) 0 Anogenital warts 1 (0.2%) 0 Bowen'sdisease 1 (0.2%) 0 Colon adenoma 1 (0.2%) 1 (0.2%) Dysplastic naevus 1(0.2%) 2 (0.4%) Fibroma 1 (0.2%) 0 Invasive ductal breast carcinoma 1(0.2%) 0 Lipoma 1 (0.2%) 1 (0.2%) Ductal adenocarcinoma of pancreas 0 1(0.2%) Haemangioma 0 1 (0.2%) Kidney angiomyolipoma 0 1 (0.2%) Mycosisfungoides 0 1 (0.2%) Non-small cell lung cancer 0 1 (0.2%) Seborrhoeickeratosis 0 2 (0.4%) Uterine leiomyoma 0 2 (0.4%) Psychiatric disorders24 (4.5%) 27 (5.3%) Anxiety 8 (1.5%) 9 (1.8%) Depression 5 (0.9%) 4(0.8%) Insomnia 4 (0.7%) 7 (1.4%) Suicidal ideation 3 (0.6%) 3 (0.6%)Alcoholism 1 (0.2%) 0 Borderline personality disorder 1 (0.2%) 0Depressed mood 1 (0.2%) 1 (0.2%) Grief reaction 1 (0.2%) 0 Psychoticdisorder 1 (0.2%) 0 Restlessness 1 (0.2%) 0 Sleep disorder 1 (0.2%) 0Stress 1 (0.2%) 2 (0.4%) Adjustment disorder with 0 1 (0.2%) depressedmood Intentional self-injury 0 1 (0.2%) Irritability 0 1 (0.2%) Mentaldisorder 0 1 (0.2%) Mixed anxiety and depressive 0 1 (0.2%) disorderPanic attack 0 1 (0.2%) Seasonal affective disorder 0 1 (0.2%) Suicideattempt 0 1 (0.2%) Metabolism and nutrition disorders 22 (4.1%) 16(3.1%) Hyperglycaemia 9 (1.7%) 1 (0.2%) Hyperlipidaemia 3 (0.6%) 0Abnormal loss of weight 1 (0.2%) 0 Decreased appetite 1 (0.2%) 2 (0.4%)Diabetes mellitus 1 (0.2%) 3 (0.6%) Gout 1 (0.2%) 2 (0.4%)Haemochromatosis 1 (0.2%) 0 Hypercholesterolaemia 1 (0.2%) 0Hyperkalaemia 1 (0.2%) 1 (0.2%) Hypcrtriglyceridaemia 1 (0.2%) 0Hyperuricaemia 1 (0.2%) 0 Hypokalaemia 1 (0.2%) 2 (0.4%) Increasedappetite 1 (0.2%) 1 (0.2%) Overweight 1 (0.2%) 0 Type 2 diabetesmellitus 1 (0.2%) 2 (0.4%) Dehydration 0 1 (0.2%) Diabetes mellitusinadequate 0 1 (0.2%) control Glucose tolerance impaired 0 1 (0.2%)Hyperhomocysteinaemia 0 1 (0.2%) Hypoglycaemia 0 1 (0.2%) Hyponatraemia0 1 (0.2%) Polydipsia 0 1 (0.2%) Type 1 diabetes mellitus 0 1 (0.2%)Vitamin D deficiency 0 1 (0.2%) Cardiac disorders 20 (3.7%) 11 (2.2%)Tachycardia 5 (0.9%) 1 (0.2%) Atrial fibrillation 4 (0.7%) 2 (0.4%)Bundle branch block left 3 (0.6%) 0 Palpitations 2 (0.4%) 0 Aortic valvestenosis 1 (0.2%) 0 Bundle branch block right 1 (0.2%) 0 Coronary arteryocclusion 1 (0.2%) 0 Defect conduction intraventricular 1 (0.2%) 0 Sinusbradycardia 1 (0.2%) 0 Supraventricular tachycardia 1 (0.2%) 0Ventricular extrasystoles 1 (0.2%) 0 Wolff-Parkinson-White syndrome 1(0.2%) 0 Atrial thrombosis 0 1 (0.2%) Atrioventricular block complete 01 (0.2%) Atrioventricular block first degree 0 2 (0.4%) Cardiac disorder0 1 (0.2%) Cardiac failure congestive 0 1 (0.2%) Coronary artery disease0 1 (0.2%) Extrasystoles 0 1 (0.2%) Left ventricular dilatation 0 1(0.2%) Sinus tachycardia 0 2 (0.4%) Eye disorders 18 (3.4%) 17 (3.3%)Cataract 5 (0.9%) 2 (0.4%) Conjunctivitis allergic 3 (0.6%) 3 (0.6%) Dryeye 2 (0.4%) 2 (0.4%) Blepharitis 1 (0.2%) 4 (0.8%) Cataract subcapsular1 (0.2%) 0 Chalazion 1 (0.2%) 0 Conjunctival haemorrhage 1 (0.2%) 1(0.2%) Conjunctival hyperaemia 1 (0.2%) 0 Diabetic retinopathy 1 (0.2%)0 Episcleritis 1 (0.2%) 0 Eye oedema 1 (0.2%) 0 Eye swelling 1 (0.2%) 0Glaucoma 1 (0.2%) 0 Macular fibrosis 1 (0.2%) 0 Ocular hyperaemia 1(0.2%) 0 Ocular hypertension 1 (0.2%) 0 Retinal degeneration 1 (0.2%) 0Vitreous detachment 1 (0.2%) 0 Blepharospasm 0 1 (0.2%) Eczema eyelids 01 (0.2%) Eye discharge 0 1 (0.2%) Myopia 0 1 (0.2%) Pupils unequal 0 1(0.2%) Visual acuity reduced 0 2 (0.4%) Ear and labyrinth disorders 13(2.4%) 13 (2.5%) Vertigo 7 (1.3%) 6 (1.2%) Ear pain 3 (0.6%) 3 (0.6%)Cerumen impaction 1 (0.2%) 0 Ear canal erythema 1 (0.2%) 0 Eardiscomfort 1 (0.2%) 0 Ear pruritus 1 (0.2%) 0 Tinnitus 1 (0.2%) 1 (0.2%)Deafness unilateral 0 1 (0.2%) Ear canal stenosis 0 1 (0.2%) Hypoacusis0 1 (0.2%) Middle ear effusion 0 1 (0.2%) Blood and lymphatic systemdisorders 10 (1.9%) 9 (1.8%) Lymphadenopathy 3 (0.6%) 2 (0.4%) Anaemia 2(0.4%) 0 Leukocytosis 2 (0.4%) 0 Thrombocytopenia 2 (0.4%) 0Neutrophilia 1 (0.2%) 0 Pancytopenia 1 (0.2%) 0 Erythropenia 0 1 (0.2%)Leukopenia 0 1 (0.2%) Lymphopenia 0 2 (0.4%) Neutropenia 0 4 (0.8%)Reproductive system and breast 9 (1.7%) 12 (2.3%) disordersDysmenorrhoea 2 (0.4%) 1 (0.2%) Bartholin's cyst 1 (0.2%) 0 Benignprostatic hyperplasia 1 (0.2%) 2 (0.4%) Breast cyst 1 (0.2%) 0 Breastmass 1 (0.2%) 1 (0.2%) Endometriosis 1 (0.2%) 0 Erectile dysfunction 1(0.2%) 0 Varicocele 1 (0.2%) 0 Acquired phimosis 0 1 (0.2%) Endometrialdisorder 0 2 (0.4%) Prostatomegaly 0 1 (0.2%) Vulvovaginal dryness 0 1(0.2%) Vulvovaginal inflammation 0 1 (0.2%) Vulvovaginal pruritus 0 2(0.4%) Hepatobiliary disorders 7 (1.3%) 10 (2.0%) Hepatic steatosis 3(0.6%) 5 (1.0%) Biliary colic 2 (0.4%) 0 Cholelithiasis 2 (0.4%) 3(0.6%) Cholecystitis acute 1 (0.2%) 0 Cholangitis 0 1 (0.2%)Cholecystitis 0 1 (0.2%) Drug-induced liver injury 0 1 (0.2%)Gallbladder polyp 0 1 (0.2%) Hepatomegaly 0 1 (0.2%) Jaundice 0 1 (0.2%)Immune system disorders 6 (1.1%) 9 (1.8%) Seasonal allergy 4 (0.7%) 6(1.2%) Allergy to arthropod bite 1 (0.2%) 2 (0.4%) Drug hypersensitivity1 (0.2%) 0 Anaphylactoid reaction 0 1 (0.2%) Renal and urinary disorders6 (1.1%) 8 (1.6%) Nephrolithiasis 4 (0.7%) 2 (0.4%) Acute kidney injury1 (0.2%) 1 (0.2%) Haematuria 1 (0.2%) 0 Cystitis noninfective 0 1 (0.2%)Glycosuria 0 1 (0.2%) Incontinence 0 1 (0.2%) Ketonuria 0 1 (0.2%)Leukocyturia 0 1 (0.2%) Micturition urgency 0 1 (0.2%) Pollakiuria 0 2(0.4%) Congenital, familial and genetic 2 (0.4%) 0 disorders Dermoidcyst 1 (0.2%) 0 Hydrocele 1 (0.2%) 0 Endocrine disorders 2 (0.4%) 3(0.6%) Hyperthyroidism 1 (0.2%) 1 (0.2%) Hypothyroidism 1 (0.2%) 0Androgen deficiency 0 1 (0.2%) Autoimmune thyroiditis 0 1 (0.2%)Pregnancy, puerperium and 1 (0.2%) 3 (0.6%) perinatal conditionsPregnancy 1 (0.2%) 2 (0.4%) Unintended pregnancy 0 1 (0.2%) Socialcircumstances 1 (0.2%) 2 (0.4%) Pregnancy of partner 1 (0.2%) 2 (0.4%)Product issues 0 3 (0.6%) Device dislocation 0 1 (0.2%) Device loosening0 1 (0.2%) Device material opacification 0 1 (0.2%) Surgical and medicalprocedures 0 1 (0.2%) Finger amputation 0 1 (0.2%) Key: AE = adverseevent, Avg = average. Note: Subjects are counted only once for any givenevent, regardless of the number of times they actually experienced theevent. Adverse events are coded using MedDRA Version 21.0. [TSFAE01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFAE01A.SAS]23OCT2018, 12:58

APPENDIX 17 Number of Subjects With Treatment-Emergent Serious AdverseEvents Through Week 56 by System Organ Class and Preferred Term; SafetyAnalysis Set (Study CNTO1959PSO3009) Guselkumab 100 mg Secukinumab 300mg Analysis set: Safety analysis set 534  511  Avg duration of follow-up(weeks)   54.90   53.67 Avg exposure (number of administrations)   14.65  14.41 Subjects with 1 or more SAEs 33 (6.2%)  37 (7.2%)  System organclass Preferred term Infections and infestations 4 (0.7%) 5 (1.0%)Appendicitis 1 (0.2%) 0 Cellulitis 1 (0.2%) 1 (0.2%) Labyrinthitis 1(0.2%) 0 Pneumonia 1 (0.2%) 1 (0.2%) Abscess limb 0 1 (0.2%)Neuroborreliosis 0 1 (0.2%) Pyelonephritis 0 1 (0.2%) Injury, poisoningand procedural complications 4 (0.7%) 4 (0.8%) Clavicle fracture 1(0.2%) 0 Ligament rupture 1 (0.2%) 0 Meniscus injury 1 (0.2%) 0 Skullfracture 1 (0.2%) 0 Femoral neck fracture 0 1 (0.2%) Foot fracture 0 1(0.2%) Tendon rupture 0 1 (0.2%) Upper limb fracture 0 1 (0.2%)Respiratory, thoracic and mediastinal disorders 4 (0.7%) 1 (0.2%)Interstitial lung disease 1 (0.2%) 0 Nasal cyst 1 (0.2%) 0 Nasal polyps1 (0.2%) 0 Pneumonia aspiration 1 (0.2%) 0 Pulmonary embolism 0 1 (0.2%)Cardiac disorders 3 (0.6%) 3 (0.6%) Atrial fibrillation 1 (0.2%) 1(0.2%) Coronary artery occlusion 1 (0.2%) 0 Wolff-Parkinson-Whitesyndrome 1 (0.2%) 0 Atrioventricular block complete 0 1 (0.2%) Cardiacfailure congestive 0 1 (0.2%) Gastrointestinal disorders 3 (0.6%) 2(0.4%) Constipation 1 (0.2%) 0 Leukoplakia oral 1 (0.2%) 0 Umbilicalhernia 1 (0.2%) 0 Crohn's disease 0 1 (0.2%) Haemorrhoids 0 1 (0.2%)Skin and subcutaneous tissue disorders 3 (0.6%) 1 (0.2%) Chroniccutaneous lupus erythematosus 1 (0.2%) 0 Drug eruption 1 (0.2%) 0 Rashmorbilliform 1 (0.2%) 0 Psoriasis 0 1 (0.2%) General disorders andadministration site 2 (0.4%) 3 (0.6%) conditions General physical healthdeterioration 1 (0.2%) 0 Non-cardiac chest pain 1 (0.2%) 1 (0.2%) Chestpain 0 1 (0.2%) Exercise tolerance decreased 0 1 (0.2%) Hepatobiliarydisorders 2 (0.4%) 3 (0.6%) Cholecystitis acute 1 (0.2%) 0Cholelithiasis 1 (0.2%) 1 (0.2%) Cholecystitis 0 1 (0.2%) Drug-inducedliver injury 0 1 (0.2%) Musculoskeletal and connective tissue 2 (0.4%) 5(1.0%) disorders Osteoarthritis 1 (0.2%) 1 (0.2%) Rotator cuff syndrome1 (0.2%) 0 Intervertebral disc protrusion 0 2 (0.4%) Spinal columnstenosis 0 1 (0.2%) Spinal osteoarthritis 0 1 (0.2%) Reproductive systemand breast disorders 2 (0.4%) 2 (0.4%) Bartholin's cyst 1 (0.2%) 0Endometriosis 1 (0.2%) 0 Benign prostatic hyperplasia 0 1 (0.2%)Prostatomegaly 0 1 (0.2%) Vascular disorders 2 (0.4%) 1 (0.2%)Arteriosclerosis 1 (0.2%) 0 Hypotension 1 (0.2%) 0 Deep vein thrombosis0 1 (0.2%) Eye disorders 1 (0.2%) 0 Macular fibrosis 1 (0.2%) 0Investigations 1 (0.2%) 0 Electrocardiogram repolarisation 1 (0.2%) 0abnormality Neoplasms benign, malignant and unspecified 1 (0.2%) 1(0.2%) (incl cysts and polyps) Invasive ductal breast carcinoma 1 (0.2%)0 Non-small cell lung cancer 0 1 (0.2%) Nervous system disorders 1(0.2%) 1 (0.2%) Headache 1 (0.2%) 0 Cerebrovascular accident 0 1 (0.2%)Syncope 0 1 (0.2%) Psychiatric disorders 1 (0.2%) 2 (0.4%) Anxiety 1(0.2%) 1 (0.2%) Depression 0 1 (0.2%) Mixed anxiety and depressivedisorder 0 1 (0.2%) Renal and urinary disorders 1 (0.2%) 2 (0.4%) Acutekidney injury 1 (0.2%) 1 (0.2%) Nephrolithiasis 0 1 (0.2%) Immune systemdisorders 0 1 (0.2%) Anaphylactoid reaction 0 1 (0.2%) Surgical andmedical procedures 0 1 (0.2%) Finger amputation 0 1 (0.2%) Key: AE =adverse event, Avg = average. Note: Subjects are counted only once forany given event, regardless of the number of times they actuallyexperienced the event. Adverse events are coded using MedDRA Version21.0. [TSFAE04.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFAE04.SAS]23OCT2018, 12:58

APPENDIX 18 Number of Subjects With Treatment-Emergent Adverse EventsLeading to Discontinuation of Study Agent Through Week 44 by SystemOrgan Class and Preferred Term; Safety Analysis Set (StudyCNTO1959PSO3009) Guselkumab 100 mg Secukinumab 300 mg Analysis set:Safety analysis set 534  511  Avg duration of follow-up (weeks)   54.90  53.67 Avg exposure (number of administrations)   14.65   14.41Subjects with 1 or more AEs leading to 10 (1.9%)  12 (2.3%) discontinuation of study agent System organ class Preferred termNeoplasms benign, malignant and unspecified 4 (0.7%) 2 (0.4%) (inclcysts and polyps) Squamous cell carcinoma of skin 2 (0.4%) 0 Bowen'sdisease 1 (0.2%) 0 Invasive ductal breast carcinoma 1 (0.2%) 0 Mycosisfungoides 0 1 (0.2%) Non-small cell lung cancer 0 1 (0.2%) Skin andsubcutaneous tissue disorders 3 (0.6%) 2 (0.4%) Drug eruption 1 (0.2%) 0Psoriasis 1 (0.2%) 1 (0.2%) Rash morbilliform 1 (0.2%) 0 Rashmaculo-papular 0 1 (0.2%) Gastrointestinal disorders 1 (0.2%) 2 (0.4%)Colitis microscopic 1 (0.2%) 0 Crohn's disease 0 1 (0.2%) Inflammatorybowel disease 0 1 (0.2%) Investigations 1 (0.2%) 1 (0.2%) Transaminasesincreased 1 (0.2%) 0 Platelet count decreased 0 1 (0.2%) Pregnancy,puerperium and perinatal 1 (0.2%) 1 (0.2%) conditions Pregnancy 1 (0.2%)1 (0.2%) Hepatobiliary disorders 0 1 (0.2%) Drug-induced liver injury 01 (0.2%) Infections and infestations 0 1 (0.2%) Abscess limb 0 1 (0.2%)Nervous system disorders 0 1 (0.2%) Cerebrovascular accident 0 1 (0.2%)Vascular disorders 0 1 (0.2%) Deep vein thrombosis 0 1 (0.2%) Key: AE =adverse event, Avg = average. Note: Subjects are counted only once forany given event, regardless of the number of times they actuallyexperienced the event. Adverse events are coded using MedDRA Version21.0. [TSFAE05.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFAE05.SAS]23OCT2018, 12:58

APPENDIX 19 Number of Subjects With Treatment-Emergent InfectionsThrough Week 56 by System Organ Class and Preferred Term; SafetyAnalysis Set (Study CNTO1959PSO3009) Guselkumab 100 mg Secukinumab 300mg Analysis set: Safety analysis set 534  511  Avg duration of follow-up(weeks)   54.90   53.67 Avg exposure (number of administrations)   14.65  14.41 Subjects with 1 or more infections 313 (58.6%) 331 (64.8%)System organ class Preferred term Infections and infestations 308(57.7%) 323 (63.2%) Nasopharyngitis 117 (21.9%) 125 (24.5%) Upperrespiratory tract infection 83 (15.5%) 92 (18.0%) Pharyngitis 24 (4.5%)22 (4.3%) Influenza 20 (3.7%) 13 (2.5%) Bronchitis 17 (3.2%) 15 (2.9%)Oral herpes 11 (2.1%) 14 (2.7%) Urinary tract infection 11 (2.1%) 11(2.2%) Gastroenteritis 10 (1.9%) 9 (1.8%) Sinusitis 10 (1.9%) 12 (2.3%)Gastroenteritis viral 9 (1.7%) 8 (1.6%) Viral upper respiratory tractinfection 9 (1.7%) 8 (1.6%) Folliculitis 8 (1.5%) 9 (1.8%) Rhinitis 8(1.5%) 13 (2.5%) Tonsillitis 7 (1.3%) 15 (2.9%) Tinea pedis 6 (1.1%) 16(3.1%) Gastrointestinal infection 5 (0.9%) 0 Oral candidiasis 5 (0.9%)11 (2.2%) Tooth abscess 5 (0.9%) 3 (0.6%) Tooth infection 5 (0.9%) 2(0.4%) Vulvovaginal candidiasis 5 (0.9%) 13 (2.5%) Acute sinusitis 4(0.7%) 0 Cellulitis 4 (0.7%) 3 (0.6%) Conjunctivitis 4 (0.7%) 16 (3.1%)Respiratory tract infection 4 (0.7%) 2 (0.4%) Tinea versicolour 4 (0.7%)5 (1.0%) Gastrointestinal viral infection 3 (0.6%) 1 (0.2%)Periodontitis 3 (0.6%) 4 (0.8%) Pneumonia 3 (0.6%) 6 (1.2%) Cystitis 2(0.4%) 2 (0.4%) Ear infection 2 (0.4%) 5 (1.0%) Helicobacter gastritis 2(0.4%) 0 Laryngitis 2 (0.4%) 2 (0.4%) Localised infection 2 (0.4%) 1(0.2%) Otitis media 2 (0.4%) 6 (1.2%) Postoperative wound infection 2(0.4%) 0 Skin candida 2 (0.4%) 3 (0.6%) Tinea cruris 2 (0.4%) 4 (0.8%)Wound infection 2 (0.4%) 1 (0.2%) Anal abscess 1 (0.2%) 0 Anal fistulainfection 1 (0.2%) 0 Appendicitis 1 (0.2%) 0 Arthritis infective 1(0.2%) 0 Bacterial rhinitis 1 (0.2%) 0 Bacterial vulvovaginitis 1 (0.2%)0 Candida infection 1 (0.2%) 0 Conjunctivitis bacterial 1 (0.2%) 0Dermatitis infected 1 (0.2%) 2 (0.4%) Dermo-hypodermitis 1 (0.2%) 0Diverticulitis 1 (0.2%) 2 (0.4%) Enterobiasis 1 (0.2%) 0 Erysipelas 1(0.2%) 0 Furuncle 1 (0.2%) 2 (0.4%) Gangrene 1 (0.2%) 0 Gastroenteritisyersinia 1 (0.2%) 0 Genital herpes 1 (0.2%) 3 (0.6%) Gingivitis 1 (0.2%)2 (0.4%) Hordeolum 1 (0.2%) 8 (1.6%) Impetigo 1 (0.2%) 4 (0.8%)Labyrinthitis 1 (0.2%) 0 Mastitis 1 (0.2%) 0 Nasal herpes 1 (0.2%) 1(0.2%) Ophthalmic herpes zoster 1 (0.2%) 0 Paronychia 1 (0.2%) 2 (0.4%)Peritonsillar abscess 1 (0.2%) 0 Pyoderma 1 (0.2%) 0 Salmonellosis 1(0.2%) 0 Sepsis 1 (0.2%) 0 Skin bacterial infection 1 (0.2%) 0 Upperrespiratory tract infection bacterial 1 (0.2%) 0 Urinary tract infectionbacterial 1 (0.2%) 0 Viral pharyngitis 1 (0.2%) 0 Abscess 0 1 (0.2%)Abscess limb 0 1 (0.2%) Acarodermatitis 0 2 (0.4%) Angular cheilitis 0 2(0.4%) Application site cellulitis 0 1 (0.2%) Bacterial vaginosis 0 1(0.2%) Balanitis candida 0 1 (0.2%) Blister infected 0 1 (0.2%) Bodytinea 0 2 (0.4%) Bullous impetigo 0 1 (0.2%) Eczema impetiginous 0 1(0.2%) Eczema infected 0 2 (0.4%) Groin abscess 0 1 (0.2%) Helicobacterinfection 0 1 (0.2%) Herpes simplex 0 1 (0.2%) Herpes zoster 0 4 (0.8%)Neuroborreliosis 0 1 (0.2%) Onychomycosis 0 1 (0.2%) Otitis externa 0 3(0.6%) Otitis media acute 0 1 (0.2%) Perianal streptococcal infection 01 (0.2%) Peritonsillitis 0 1 (0.2%) Pharyngitis streptococcal 0 4 (0.8%)Pharyngotonsillitis 0 1 (0.2%) Pulpitis dental 0 1 (0.2%) Pyelonephritis0 1 (0.2%) Respiratory syncytial virus infection 0 1 (0.2%) Respiratorytract infection viral 0 1 (0.2%) Soft tissue infection 0 1 (0.2%)Staphylococcal skin infection 0 3 (0.6%) Subcutaneous abscess 0 2 (0.4%)Tracheobronchitis 0 1 (0.2%) Vaginal infection 0 2 (0.4%) Vulvovaginalmycotic infection 0 2 (0.4%) Respiratory, thoracic and mediastinaldisorders 12 (2.2%) 11 (2.2%) Cough 5 (0.9%) 1 (0.2%) Oropharyngeal pain3 (0.6%) 3 (0.6%) Rhinorrhoea 2 (0.4%) 5 (1.0%) Nasal congestion 1(0.2%) 0 Pneumonia aspiration 1 (0.2%) 0 Respiratory disorder 1 (0.2%) 0Nasal ulcer 0 1 (0.2%) Sinus congestion 0 1 (0.2%) Gastrointestinaldisorders 7 (1.3%) 3 (0.6%) Diarrhoea 3 (0.6%) 0 Enteritis 3 (0.6%) 0Dental caries 1 (0.2%) 0 Aphthous ulcer 0 2 (0.4%) Apical granuloma 0 1(0.2%) General disorders and administration site 5 (0.9%) 8 (1.6%)conditions Influenza like illness 3 (0.6%) 5 (1.0%) Pyrexia 2 (0.4%) 2(0.4%) Nodule 0 1 (0.2%) Neoplasms benign, malignant and unspecified 4(0.7%) 2 (0.4%) (incl cysts and polyps) Skin papilloma 3 (0.6%) 2 (0.4%)Anogenital warts 1 (0.2%) 0 Skin and subcutaneous tissue disorders 4(0.7%) 10 (2.0%) Acne 1 (0.2%) 0 Intertrigo 1 (0.2%) 7 (1.4%)Onycholysis 1 (0.2%) 0 Skin ulcer 1 (0.2%) 1 (0.2%) Dermal cyst 0 1(0.2%) Psoriasis 0 1 (0.2%) Congenital, familial and genetic disorders 1(0.2%) 0 Dermoid cyst 1 (0.2%) 0 Reproductive system and breastdisorders 1 (0.2%) 0 Bartholin's cyst 1 (0.2%) 0 Eye disorders 0 2(0.4%) Blepharitis 0 2 (0.4%) Nervous system disorders 0 1 (0.2%) Postherpetic neuralgia 0 1 (0.2%) Renal and urinary disorders 0 1 (0.2%)Cystitis noninfective 0 1 (0.2%) Vascular disorders 0 1 (0.2%) Phlebitissuperficial 0 1 (0.2%) Key: Avg = average. Note: Subjects are countedonly once for any given event, regardless of the number of times theyactually experienced the event. Adverse events are coded using MedDRAVersion 21.0. [TSFINFE01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFINFE01.SAS]23OCT2018, 12:59

APPENDIX 20 Number of Subjects With Treatment-Emergent InfectionsRequiring Oral or Parenteral Antimicrobial Treatment Through Week 56 bySystem Organ Class and Preferred Term; Safety Analysis Set (StudyCNTO1959PSO3009) Guselkumab 100 mg Secukinumab 300 mg Analysis set:Safety analysis set 534  511  Avg duration of follow-up (weeks)   54.90  53.67 Avg exposure (number of administrations)   14.65   14.41Subjects with 1 or more infections requiring 118 (22.1%)  147 (28.8%) treatment System organ class Preferred term Infections and infestations116 (21.7%)  139 (27.2%)  Upper respiratory tract infection 19 (3.6%) 28 (5.5%)  Bronchitis 14 (2.6%)  12 (2.3%)  Pharyngitis 13 (2.4%)  10(2.0%)  Nasopharyngitis 11 (2.1%)  12 (2.3%)  Urinary tract infection 9(1.7%) 9 (1.8%) Tonsillitis 5 (0.9%) 13 (2.5%)  Cellulitis 4 (0.7%) 3(0.6%) Sinusitis 4 (0.7%) 4 (0.8%) Tooth abscess 4 (0.7%) 3 (0.6%) Toothinfection 4 (0.7%) 1 (0.2%) Acute sinusitis 3 (0.6%) 0 Influenza 3(0.6%) 2 (0.4%) Pneumonia 3 (0.6%) 6 (1.2%) Respiratory tract infection3 (0.6%) 0 Viral upper respiratory tract infection 3 (0.6%) 1 (0.2%)Folliculitis 2 (0.4%) 3 (0.6%) Gastroenteritis 2 (0.4%) 0 Localisedinfection 2 (0.4%) 1 (0.2%) Periodontitis 2 (0.4%) 2 (0.4%)Postoperative wound infection 2 (0.4%) 0 Wound infection 2 (0.4%) 0Arthritis infective 1 (0.2%) 0 Bacterial rhinitis 1 (0.2%) 0 Bacterialvulvovaginitis 1 (0.2%) 0 Conjunctivitis bacterial 1 (0.2%) 0 Cystitis 1(0.2%) 2 (0.4%) Dermo-hypodermitis 1 (0.2%) 0 Diverticulitis 1 (0.2%) 2(0.4%) Ear infection 1 (0.2%) 4 (0.8%) Erysipelas 1 (0.2%) 0Gastroenteritis yersinia 1 (0.2%) 0 Gingivitis 1 (0.2%) 2 (0.4%)Helicobacter gastritis 1 (0.2%) 0 Hordeolum 1 (0.2%) 2 (0.4%) Impetigo 1(0.2%) 2 (0.4%) Laryngitis 1 (0.2%) 1 (0.2%) Mastitis 1 (0.2%) 0Ophthalmic herpes zoster 1 (0.2%) 0 Oral candidiasis 1 (0.2%) 1 (0.2%)Otitis media 1 (0.2%) 6 (1.2%) Paronychia 1 (0.2%) 1 (0.2%)Peritonsillar abscess 1 (0.2%) 0 Pyoderma 1 (0.2%) 0 Salmonellosis 1(0.2%) 0 Sepsis 1 (0.2%) 0 Skin bacterial infection 1 (0.2%) 0 Upperrespiratory tract infection bacterial 1 (0.2%) 0 Urinary tract infectionbacterial 1 (0.2%) 0 Viral pharyngitis 1 (0.2%) 0 Abscess 0 1 (0.2%)Abscess limb 0 1 (0.2%) Application site cellulitis 0 1 (0.2%) Blisterinfected 0 1 (0.2%) Bullous impetigo 0 1 (0.2%) Conjunctivitis 0 5(1.0%) Dermatitis infected 0 1 (0.2%) Furuncle 0 1 (0.2%)Gastroenteritis viral 0 1 (0.2%) Gastrointestinal viral infection 0 1(0.2%) Groin abscess 0 1 (0.2%) Helicobacter infection 0 1 (0.2%) Herpeszoster 0 1 (0.2%) Neuroborreliosis 0 1 (0.2%) Otitis media acute 0 1(0.2%) Perianal streptococcal infection 0 1 (0.2%) Peritonsillitis 0 1(0.2%) Pharyngitis streptococcal 0 3 (0.6%) Pharyngotonsillitis 0 1(0.2%) Pulpitis dental 0 1 (0.2%) Pyelonephritis 0 1 (0.2%) Respiratorysyncytial virus infection 0 1 (0.2%) Rhinitis 0 1 (0.2%) Soft tissueinfection 0 1 (0.2%) Staphylococcal skin infection 0 1 (0.2%)Subcutaneous abscess 0 2 (0.4%) Tracheobronchitis 0 1 (0.2%) Vaginalinfection 0 1 (0.2%) Vulvovaginal candidiasis 0 1 (0.2%) Skin andsubcutaneous tissue disorders 3 (0.6%) 4 (0.8%) Acne 1 (0.2%) 0Intertrigo 1 (0.2%) 1 (0.2%) Skin ulcer 1 (0.2%) 1 (0.2%) Dermal cyst 01 (0.2%) Psoriasis 0 1 (0.2%) Gastrointestinal disorders 1 (0.2%) 1(0.2%) Diarrhoea 1 (0.2%) 0 Apical granuloma 0 1 (0.2%) Generaldisorders and administration site 1 (0.2%) 1 (0.2%) conditions Influenzalike illness 1 (0.2%) 0 Pyrexia 0 1 (0.2%) Reproductive system andbreast disorders 1 (0.2%) 0 Bartholin's cyst 1 (0.2%) 0 Respiratory,thoracic and mediastinal disorders 1 (0.2%) 4 (0.8%) Pneumoniaaspiration 1 (0.2%) 0 Nasal ulcer 0 1 (0.2%) Oropharyngeal pain 0 3(0.6%) Renal and urinary disorders 0 1 (0.2%) Cystitis noninfective 0 1(0.2%) Vascular disorders 0 1 (0.2%) Phlebitis superficial 0 1 (0.2%)Key: Avg = average. Note: Subjects are counted only once for any givenevent, regardless of the number of times they actually experienced theevent. Adverse events are coded using MedDRA Version 21.0.[TSFINFE03.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFINFE03.SAS]23OCT2018, 12:59

APPENDIX 21 Number of Subjects With Treatment-Emergent SeriousInfections Through Week 56 by System Organ Class and Preferred Term;Safety Analysis Set (Study CNTO1959PSO3009) Guselkumab 100 mgSecukinumab 300 mg Analysis set: Safety analysis set 534 511  Avgduration of follow-up (weeks) 54.90   53.67 Avg exposure (number ofadministrations) 14.65   14.41 Subjects with 1 or more seriousinfections 6 (1.1%) 5 (1.0%) System organ class Preferred termInfections and infestations 4 (0.7%) 5 (1.0%) Appendicitis 1 (0.2%) 0Cellulitis 1 (0.2%) 1 (0.2%) Labyrinthitis 1 (0.2%) 0 Pneumonia 1 (0.2%)1 (0.2%) Abscess limb 0 1 (0.2%) Neuroborreliosis 0 1 (0.2%)Pyelonephritis 0 1 (0.2%) Reproductive system and breast disorders 1(0.2%) 0 Bartholin's cyst 1 (0.2%) 0 Respiratory, thoracic andmediastinal disorders 1 (0.2%) 0 Pneumonia aspiration 1 (0.2%) 0 Key:Avg = average. Note: Subjects are counted only once for any given event,regardless of the number of times they actually experienced the event.Adverse events are coded using MedDRA Version 21.0. [TSFINFE02.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFINFE02.SAS]23OCT2018, 12:59

APPENDIX 22 Number of Subjects With Treatment-Emergent Adverse Events ofPsoriasis Through Week 56 by MedDRA Lower Level Term Category; SafetyAnalysis Set (Study CNTO1959PSO3009) Guselkumab 100 mg Secukinumab 300mg Analysis set: Safety analysis set 534 511 Avg duration of follow-up(weeks) 54.90 53.67 Avg exposure (number of administrations) 14.65 14.41Subjects with 1 or more AEs of psoriasis 4 (0.7%) 11 (2.2%) Lower levelterm category Worsening or exacerbation of psoriasis 4 (0.7%) 11 (2.2%)Key: AE = adverse event, Avg = average. Note: Subjects are counted onlyonce for any given event, regardless of the number of times theyactually experienced the event. Adverse events are coded using MedDRAVersion 21.0. [TSFAE08.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFAE08.SAS]23OCT2018, 12:59

APPENDIX 23 Summary of Injection-Site Reactions Through Week 56 byIntensity; Treated Subjects by Study Agent Injection Received (StudyCNTO1959PSO3009) Placebo Guselkumab Secukinumab Injections InjectionsInjections Analysis set: Treated subjects by study agent 534 534 511injection received Avg number of injections 22.5 6.8 28.8 Subjects with1 or more injection-site reactions 20 (3.7%) 13 (2.4%) 20 (3.9%) Totalnumber of injections 11998 3644 14722 Injections with injection-sitereactions 32 (0.3%) 19 (0.5%) 63 (0.4%) Mild 30 (0.3%) 19 (0.5%) 55(0.4%) Moderate  2 (<0.1%) 0  8 (0.1%) Severe 0 0 0 [TSFIR01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFIR01.SAS]23OCT2018, 12:59

APPENDIX 24 Summary of Injection-Site Reactions Through Week 56 bySystem Organ Class and Preferred Term; Treated Subjects by Study AgentInjection Received (Study CNTO1959PSO3009) Placebo GuselkumabSecukinumab Injections Injections Injections Analysis set: Treated 534534 511 subjects by study agent injection received Avg number ofinjections 22.5 6.8 28.8 Total number of injections 11998 3644 14722Injections with 32 (0.3%)  19 (0.5%)  63 (0.4%)  injection-sitereactions Subjects with 1 or more 20 (3.7%)  13 (2.4%)  20 (3.9%) injection-site reactions System organ class Preferred term Generaldisorders and 20 (3.7%)  13 (2.4%)  20 (3.9%)  administration siteconditions Injection site erythema 8 (1.5%) 6 (1.1%) 7 (1.4%) Injectionsite pruritus 3 (0.6%) 4 (0.7%) 0 Injection site haematoma 3 (0.6%) 3(0.6%) 5 (1.0%) Injection site swelling 3 (0.6%) 3 (0.6%) 1 (0.2%)Injection site pain 5 (0.9%) 2 (0.4%) 6 (1.2%) Injection siteextravasation 0 1 (0.2%) 0 Injection site induration 2 (0.4%) 1 (0.2%) 0Injection site rash 0 1 (0.2%) 0 Injection site bruising 3 (0.6%) 0 2(0.4%) Injection site haemorrhage 1 (0.2%) 0 2 (0.4%) Injection siteinflammation 0 0 1 (0.2%) Injection site oedema 1 (0.2%) 0 2 (0.4%)[TSFIR02.RTF][CNTO1959\PSO3009\DBR_Week_056\RE_WEEK_056_CSR\PROD\TSFIR02.SAS]23OCT2018, 12:59

APPENDIX 25 Number of Subjects with 1 or More Post-Baseline SuicidalIdeation or Suicidal Behavior Through Week 56; Safety Analysis Set(Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300 mg Analysisset: Safety analysis set 534  511  Suicidal ideation or behavior 8(1.5%) 8 (1.6%) Suicidal ideation 5 (0.9%) 4 (0.8%) 1 - Wish to be dead2 (0.4%) 3 (0.6%) 2 - Non-specific active suicidal thoughts 1 (0.2%) 1(0.2%) 3 - Active suicidal ideation with any 1 (0.2%) 0 methods (notplan) without intent to act 4 - Active suicidal ideation with some 0 0intent to act, without specific plan 5 - Active suicidal ideation withspecific 0 0 plan and intent Suicidal behavior 3 (0.6%) 4 (0.8%) 6 -Preparatory acts or behavior 1 (0.2%) 1 (0.2%) 7 - Aborted attempt 1(0.2%) 0 8 - Interrupted attempt 1 (0.2%) 0 9 - Non-fatal suicideattempt 0 2 (0.4%) 10 - Completed suicide 0 0 Note 1: Each subject iscounted only once in the above table, based on the most severepostbaseline eC-SSRS score. Note 2: The categories of suicidal ideationor behavior, suicidal ideation, and suicidal behavior are based on theeC-SSRS and AE. Note 3: Score 1 to 9 are only based the eC-SSRS, notincluding AE. Completed suicide is from AE.[TSFECSSRS01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PROD\TSFECSSRS01.SAS]23OCT2018, 13:02Data Summary of Patients with Psoriatic Arthritis (PsA) in Addition toPsO:

TABLE 5 Table 5 -TEFPASI13A_PSA: Summary of PASI Responses Through Week56 by Visit; Full Analysis Set (Study CNTO01959PSO3009) GuselkumabSecukinumab 100 mg 300 mg Full analysis set with PSA 97 79 Week 1 N 9779 100% improvement  0  0 ≥90% improvement  0  0 ≥75% improvement  0  0≥50% improvement 6 (6.2%) 5 (6.3%) Week 2 N 97 79 100% improvement 1(1.0%) 1 (1.3%) ≥90% improvement 1 (1.0%) 1 (1.3%) ≥75% improvement 2(2.1%) 5 (6.3%) ≥50% improvement 28 (28.9%) 28 (35.4%) Week 3 N 97 79100% improvement 3 (3.1%) 1 (1.3%) ≥90% improvement 8 (8.2%) 5 (6.3%)≥75% improvement 20 (20.6%) 13 (16.5%) ≥50% improvement 46 (47.4%) 47(59.5%) Week 4 N 97 79 100% improvement 6 (6.2%) 3 (3.8%) ≥90%improvement 14 (14.4%) 7 (8.9%) ≥75% improvement 33 (34.0%) 30 (38.0%)≥50% improvement 68 (70.1%) 60 (75.9%) Week 8 N 97 79 100% improvement17 (17.5%) 19 (24.1%) ≥90% improvement 41 (42.3%) 44 (55.7%) ≥75%improvement 71 (73.2%) 64 (81.0%) ≥50% improvement 92 (94.8%) 77 (97.5%)Week 12 N 97 79 100% improvement 37 (38.1%) 31 (39.2%) ≥90% improvement69 (71.1%) 57 (72.2%) ≥75% improvement 89 (91.8%) 72 (91.1%) ≥50%improvement 96 (99.0%) 76 (96.2%) Week 16 N 97 79 100% improvement 42(43.3%) 37 (46.8%) ≥90% improvement 70 (72.2%) 59 (74.7%) ≥75%improvement 91 (93.8%) 74 (93.7%) ≥50% improvement 95 (97.9%) 76 (96.2%)Week 20 N 97 79 100% improvement 47 (48.5%) 43 (54.4%) ≥90% improvement74 (76.3%) 60 (75.9%) ≥75% improvement 89 (91.8%) 71 (89.9%) ≥50%improvement 95 (97.9%) 74 (93.7%) Week 24 N 97 79 100% improvement 56(57.7%) 36 (45.6%) ≥90% improvement 76 (78.4%) 59 (74.7%) ≥75%improvement 92 (94.8%) 70 (88.6%) ≥50% improvement 95 (97.9%) 71 (89.9%)Week 28 N 97 79 100% improvement 53 (54.6%) 38 (48.1%) ≥90% improvement80 (82.5%) 61 (77.2%) ≥75% improvement 89 (91.8%) 72 (91.1%) ≥50%improvement 94 (96.9%) 72 (91.1%) Week 32 N 97 79 100% improvement 53(54.6%) 38 (48.1%) ≥90% improvement 80 (82.5%) 58 (73.4%) ≥75%improvement 92 (94.8%) 68 (86.1%) ≥50% improvement 95 (97.9%) 72 (91.1%)Week 36 N 97 79 100% improvement 54 (55.7%) 36 (45.6%) ≥90% improvement78 (80.4%) 59 (74.7%) ≥75% improvement 92 (94.8%) 68 (86.1%) ≥50%improvement 94 (96.9%) 71 (89.9%) Week 40 N 97 79 100% improvement 53(54.6%) 36 (45.6%) ≥90% improvement 79 (81.4%) 56 (70.9%) ≥75%improvement 90 (92.8%) 67 (84.8%) ≥50% improvement 95 (97.9%) 69 (87.3%)Week 44 N 97 79 100% improvement 55 (56.7%) 34 (43.0%) ≥90% improvement79 (81.4%) 55 (69.6%) ≥75% improvement 91 (93.8%) 68 (86.1%) ≥50%improvement 95 (97.9%) 70 (88.6%) Week 48 N 97 79 100% improvement 55(56.7%) 35 (44.3%) ≥90% improvement 80 (82.5%) 50 (63.3%) ≥75%improvement 93 (95.9%) 65 (82.3%) ≥50% improvement 95 (97.9%) 68 (86.1%)Week 56 N 97 79 100% improvement 39 (40.2%) 24 (30.4%) ≥90% improvement66 (68.0%) 33 (41.8%) ≥75% improvement 81 (83.5%) 50 (63.3%) ≥50%improvement 87 (89.7%) 61 (77.2%)[TEFPASI13A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TEFPASI13A_PSA.SAS]07DEC2018,18:12

TABLE 6 Table 6 - TSICM01A_PSA: Summary of Previous PsoriasisMedications and Therapies by Medication Category; Full Analysis Set(Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300 mg Total Fullanalysis set with PSA 97 79 176 Topical agents N 97 79 176 Never Used 3(3.1%) 6 (7.6%) 9 (5.1%) Ever Used 94 (96.9%) 73 (92.4%) 167 (94.9%) Phototherapy (PUVA or UVB) N 97 78 175 Never Used 40 (41.2%) 42 (53.8%)82 (46.9%) Ever Used 57 (58.8%) 36 (46.2%) 93 (53.1%) Non-biologicsystemic (PUVA, methotrexate, cyclosporine, acitretin, apremilast, ortofacitinib) N 97 79 176 Never Used 26 (26.8%) 18 (22.8%) 44 (25.0%) ≥1therapy 71 (73.2%) 61 (77.2%) 132 (75.0%)  ≥2 therapies 41 (42.3%) 33(41.8%) 74 (42.0%) ≥3 therapies 18 (18.6%) 17 (21.5%) 35 (19.9%) ≥4therapies 3 (3.1%) 1 (1.3%) 4 (2.3%) Biologics (etanercept, infliximab,alefacept, efalizumab, ustekinumab, briakinumab, ixekizumab, adalimumab,brodalumab, tildrakizumab, or risankizumab) N 97 79 176 Never Used 56(57.7%) 45 (57.0%) 101 (57.4%)  Ever Used 41 (42.3%) 34 (43.0%) 75(42.6%) Non-biologic systemic or biologics N 97 79 176 Never Used 19(19.6%) 11 (13.9%) 30 (17.0%) Ever Used 78 (80.4%) 68 (86.1%) 146(83.0%)  Anti-TNFα agent (etanercept, infliximab, adalimumab) N 97 79176 Never Used 67 (69.1%) 54 (68.4%) 121 (68.8%)  Ever Used 30 (30.9%)25 (31.6%) 55 (31.3%) IL-12/23 inhibitors (ustekinumab, briakinumab,tildrakizumab, risankizumab) N 97 79 176 Never Used 85 (87.6%) 66(83.5%) 151 (85.8%)  Ever Used 12 (12.4%) 13 (16.5%) 25 (14.2%) IL-17inhibitors (ixekizumab, brodalumab) N 97 79 176 Never Used 81 (83.5%) 64(81.0%) 145 (82.4%)  Ever Used 16 (16.5%) 15 (19.0%) 31 (17.6%)[TSICM01A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TSICM01A_PSA.SAS]07DEC2018, 18:00

TABLE 7 Table 7 - TSIDEM01_PSA: Summary of Demographics and BaselineCharacteristics; Full Analysis Set (Study CNTO1959PSO3009) GuselkumabSecukinumab 100 mg 300 mg Total Full analysis set 97 79 176 with PSAAge, years N 97 79 176 Mean (SD) 50.7 (12.01) 46.9 (14.04) 49.0 (13.06)Median 52.0 47.0 48.5 Range (20; 77) (20; 74) (20; 77) IQ range (41.0;59.0) (35.0; 59.0) (40.0; 59.0) <45 years 29 (29.9%) 38 (48.1%) 67(38.1%) ≥45 to <65 years 53 (54.6%) 33 (41.8%) 86 (48.9%) ≥65 years 15(15.5%)  8 (10.1%) 23 (13.1%) Sex N 97 79 176 Female 30 (30.9%) 33(41.8%) 63 (35.8%) Male 67 (69.1%) 46 (58.2%) 113 (64.2%)  Race N 97 79176 American Indian or 0 1 (1.3%) 1 (0.6%) Alaska Native Asian 2 (2.1%)3 (3.8%) 5 (2.8%) Black or African 2 (2.1%) 0 2 (1.1%) American White 91(93.8%) 75 (94.9%) 166 (94.3%)  Other 2 (2.1%) 0 2 (1.1%) Ethnicity N 9779 176 Hispanic or Latino 4 (4.1%) 4 (5.1%) 8 (4.5%) Not Hispanic orLatino 93 (95.9%) 75 (94.9%) 168 (95.5%)  Weight, kg N 97 79 176 Mean(SD) 89.20 87.96 88.64 (21.231) (21.376) (21.244) Median 89.00 85.1086.75 Range (50.0; 158.9) (53.8; 177.6) (50.0; 177.6) IQ range (73.50;(73.00; (73.25; 100.00) 98.30) 100.00) ≤90 kg 52 (53.6%) 47 (59.5%) 99(56.3%) >90 kg 45 (46.4%) 32 (40.5%) 77 (43.8%) Height, cm N 97 79 176Mean (SD) 174.1 (10.05) 171.5 (8.79) 172.9 (9.57) Median 174.4 172.0173.0 Range (152; 192) (148; 196) (148; 196) IQ range (168.0; (165.1;(167.0; 182.8) 177.0) 179.0) Body mass index, kg/m² N 97 79 176 Mean(SD) 29.3 (6.04) 29.8 (6.81) 29.6 (6.38) Median 28.4 28.8 28.7 Range(17; 48) (20; 65) (17; 65) IQ range (25.4; 32.3) (25.1; 33.2) (25.2;32.8) Normal <25 kg/m² 20 (20.6%) 18 (22.8%) 38 (21.6%) Overweight ≥25to 41 (42.3%) 24 (30.4%) 65 (36.9%) <30 kg/m² Obese ≥30 kg/m² 36 (37.1%)37 (46.8%) 73 (41.5%) Key: IQ = Interquartile[TSIDEM01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TSIDEM01_PSA.SAS]07DEC2018, 17:53

TABLE 8 Table 8 - TEFPASI13A _PSA: Summary of PASI Responses ThroughWeek 56 by Visit; Full Analysis Set (Study CNT01959PSO3009) GuselkumabSecukinumab 100 mg 300 mg Full analysis set with PSA 97 79 Week 1 N 9779 100% improvement 0 0 ≥90% improvement 0 0 ≥75% improvement 0 0 ≥50%improvement 6 (6.2%) 5 (6.3%) Week 2 N 97 79 100% improvement 1 (1.0%) 1(1.3%) ≥90% improvement 1 (1.0%) 1 (1.3%) ≥75% improvement 2 (2.1%) 5(6.3%) ≥50% improvement 28 (28.9%) 28 (35.4%) Week 3 N 97 79 100%improvement 3 (3.1%) 1 (1.3%) ≥90% improvement 8 (8.2%) 5 (6.3%) ≥75%improvement 20 (20.6%) 13 (16.5%) ≥50% improvement 46 (47.4%) 47 (59.5%)Week 4 N 97 79 100% improvement 6 (6.2%) 3 (3.8%) ≥90% improvement 14(14.4%) 7 (8.9%) ≥75% improvement 33 (34.0%) 30 (38.0%) ≥50% improvement68 (70.1%) 60 (75.9%) Week 8 N 97 79 100% improvement 17 (17.5%) 19(24.1%) ≥90% improvement 41 (42.3%) 44 (55.7%) ≥75% improvement 71(73.2%) 64 (81.0%) ≥50% improvement 92 (94.8%) 77 (97.5%) Week 12 N 9779 100% improvement 37 (38.1%) 31 (39.2%) ≥90% improvement 69 (71.1%) 57(72.2%) ≥75% improvement 89 (91.8%) 72 (91.1%) ≥50% improvement 96(99.0%) 76 (96.2%) Week 16 N 97 79 100% improvement 42 (43.3%) 37(46.8%) ≥90% improvement 70 (72.2%) 59 (74.7%) ≥75% improvement 91(93.8%) 74 (93.7%) ≥50% improvement 95 (97.9%) 76 (96.2%) Week 20 N 9779 100% improvement 47 (48.5%) 43 (54.4%) ≥90% improvement 74 (76.3%) 60(75.9%) ≥75% improvement 89 (91.8%) 71(89.9%) ≥50% improvement 95(97.9%) 74 (93.7%) Week 24 N 97 79 100% improvement 56 (57.7%) 36(45.6%) ≥90% improvement 76 (78.4%) 59 (74.7%) ≥75% improvement 92(94.8%) 70 (88.6%) ≥50% improvement 95 (97.9%) 71 (89.9%) Week 28 N 9779 100% improvement 53 (54.6%) 38 (48.1%) ≥90% improvement 80 (82.5%) 61(77.2%) ≥75% improvement 89 (91.8%) 72 (91.1%) ≥50% improvement 94(96.9%) 72 (91.1%) Week 32 N 97 79 100% improvement 53 (54.6%) 38(48.1%) ≥90% improvement 80 (82.5%) 58 (73.4%) ≥75% improvement 92(94.8%) 68 (86.1%) ≥50% improvement 95 (97.9%) 72 (91.1%) Week 36 N 9779 100% improvement 54 (55.7%) 36 (45.6%) ≥90% improvement 78 (80.4%) 59(74.7%) ≥75% improvement 92 (94.8%) 68 (86.1%) ≥50% improvement 94(96.9%) 71 (89.9%) Week 40 N 97 79 100% improvement 53 (54.6%) 36(45.6%) ≥90% improvement 79 (81.4%) 56 (70.9%) ≥75% improvement 90(92.8%) 67 (84.8%) ≥50% improvement 95 (97.9%) 69 (87.3%) Week 44 N 9779 100% improvement 55 (56.7%) 34 (43.0%) ≥90% improvement 79 (81.4%) 55(69.6%) ≥75% improvement 91 (93.8%) 68 (86.1%) ≥50% improvement 95(97.9%) 70 (88.6%) Week 48 N 97 79 100% improvement 55 (56.7%) 35(44.3%) ≥90% improvement 80 (82.5%) 50 (63.3%) ≥75% improvement 93(95.9%) 65 (82.3%) ≥50% improvement 95 (97.9%) 68 (86.1%) Week 56 N 9779 100% improvement 39 (40.2%) 24 (30.4%) ≥90% improvement 66 (68.0%) 33(41.8%) ≥75% improvement 81 (83.5%) 50 (63.3%) ≥50% improvement 87(89.7%) 61 (77.2%)[TEFPASI13A.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TEFPASI13A_PSA.SAS]07DEC2018, 18:12

TABLE 9 Table 9 - TSFAE_PSA: Number of Subjects with Treatment-EmergentAdverse Events Through Week 56; PSA Subjects in Safety Analysis Set(Study CNTO1959PSO3009) Guselkumab Secukinumab 100 mg 300 mg Safetyanalysis set, with PSA 97 79 Avg duration of follow-up (weeks) 55.3652.68 Avg exposure (number of administrations) 14.76 14.13 Subjects with1 or more AEs 73 (75.3%) 67 (84.8%) Subjects with 1 or more SAEs 3(3.1%) 11 (13.9%) Subjects with 1 or more AEs leading to discontinuationof study agent 1 (1.0%) 3 (3.8%) Subjects with 1 or more infections 54(55.7%) 54 (68.4%) Subjects with 1 or more serious infections 0 2 (2.5%)Key: AE = adverse event, Avg = average. Note: Subjects are counted onlyonce for any given event, regardless of the number of times theyactually experienced the event. Adverse events are coded using MedDRAVersion 21.0.[TSFAE01.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TSFAE_PSA.SAS]07DEC2018, 12:37

TABLE 10 Table 10 - TSIDEM04_PSA: Summary of Psoriasis Baseline ClinicalDisease Characteristics; Full Analysis Set (Study CNTO1959PSO3009)Guselkumab Secukinumab 100 mg 300 mg Total Full analysis set with PSA 9779 176 Psoriasis disease duration (years) N 97 79 176 Mean (SD) 21.9(11.25) 20.0 (13.46) 21.1 (12.29) Median 21.0 17.0 20.0 Range (1; 48)(1; 57) (1; 57) IQ range (14.7; 27.0) (10.0; 28.0) (12.0; 27.5)Psoriasis disease duration (years) N 97 79 176 <15 years 25 (25.8%) 31(39.2%) 56 (31.8%) ≥15 years 72 (74.2%) 48 (60.8%) 120 (68.2%)  Age atdiagnosis (years) N 97 79 176 Mean (SD) 28.9 (13.37) 26.9 (13.28) 28.0(13.33) Median 27.0 25.0 27.0 Range (5; 67) (6; 61) (5; 67) IQ range(18.0; 37.0) (16.0; 34.0) (17.5; 36.0) Age at diagnosis (years) N 97 79176 <25 years 40 (41.2%) 36 (45.6%) 76 (43.2%) ≥25 years 57 (58.8%) 43(54.4%) 100 (56.8%)  Psoriatic arthritis N 97 79 176 Yes 97 79 176(100.0%) (100.0%) (100.0%) No 0 0 0 BSA (%) N 97 79 176 Mean (SD) 27.3(13.16) 25.0 (13.29) 26.3 (13.24) Median 23.0 21.0 23.0 Range (10; 74)(10; 68) (10; 74) IQ range (17.0; 36.0) (15.0; 32.0) (16.5; 34.5) BSA N97 79 176 <20% 26 (26.8%) 36 (45.6%) 62 (35.2%) ≥20% 71 (73.2%) 43(54.4%) 114 (64.8%)  IGA score N 97 79 176 Cleared (0) 0 0 0 Minimal (1)0 0 0 Mild (2) 0 0 0 Moderate (3) 69 (71.1%) 57 (72.2%) 126 (71.6%) Severe (4) 28 (28.9%) 22 (27.8%) 50 (28.4%) IGA score N 97 79 176 <4 69(71.1%) 57 (72.2%) 126 (71.6%)  =4 28 (28.9%) 22 (27.8%) 50 (28.4%) PASIscore (0-72) N 97 79 176 Mean (SD) 21.6 (8.29) 20.2 (7.03) 21.0 (7.76)Median 18.8 18.0 18.6 Range (12; 59) (12; 50) (12; 59) IQ range (15.7;25.5) (16.0; 22.0) (15.9; 24.3) PASI score N 97 79 176 <20 53 (54.6%) 51(64.6%) 104 (59.1%)  ≥20 44 (45.4%) 28 (35.4%) 72 (40.9%) Key: IQ =Interquartile[TSIDEM04.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TSIDEM04_PSA.SAS]07DEC2018, 17:53

TABLE 11 Table 11 - TEFFECACY PSA: _ Efficacy Guselkumab Secukinumab 95%Endpoint 100 mg 300 mg Difference CI PASI 90 at WEEK 48 84.5% (451/534)70.0% (360/514) 14.4 (9.2, 19.6) Psoriatic arthritis 82.5% (80/97) 63.3% (50/79)  19.2 (5.0, 33.4) PASI 75 at WEEK 12 AND WEEK 48 84.6%(452/534) 80.2% (412/514) 4.5 (−0.3, 9.3) Psoriatic arthritis 90.7%(88/97)  78.5% (62/79)  12.2 (0.3, 24.1) PASI 90 at WEEK 12 69.1%(369/534) 76.1% (391/514) −7 (−12.5, −1.4) Psoriatic arthritis 71.1%(69/97)  72.2% (57/79)  −1 (−15.5, 13.5) PASI 75 at WEEK 12 89.3%(477/534) 91.6% (471/514) −2.3 (−6.0, 1.4) Psoriatic arthritis 91.8%(89/97)  91.1% (72/79)  0.6 (−8.9, 10.1) PASI 100 at WEEK 48 58.2%(311/534) 48.4% (249/514) 9.8 (3.6, 16.0) Psoriatic arthritis 56.7%(55/97)  44.3% (35/79)  12.4 (−3.5, 28.3) IGA 0 at WEEK 48 62.2%(332/534) 50.4% (259/514) 11.8 (5.6, 17.9) Psoriatic arthritis 58.8%(57/97)  45.6% (36/79)  13.2 (−2.7, 29.1) IGA 0/1 at WEEK 48 85.0%(454/534) 74.9% (385/514) 10.1 (5.1, 15.1) Psoriatic arthritis 88.7%(86/97)  73.4% (58/79)  15.2 (2.5, 28.0)[TEFFECACY_PSA.RTF][CNTO1959\PSO3009\DBR_WEEK_056\RE_WEEK_056_CSR\PDEV\TEFFECACY_PSA.SAS]08DEC2018, 10:03PASI 90/PASI 100 and IGA 0/1 Organized by Weight Quartiles

TABLE 12 PASI 90 at Week 48 by weight quartiles Weight CategoryGuselkumab Secukinumab Treatment Lower Upper (kg) 100 mg 300 mgDifference Limit Limit <=74 86.7% 75.6% 11.1% 0.9% 21.3% (124/143)(93/123) >74-<=87 89.1% 73.0% 16.0% 6.0% 26.0% (106/119)(103/141) >87-<=100 80.3% 71.0% 9.3% −1.9% 20.6% (106/132) (88/124) >10082.1% 61.3% (115/140) (76/124) 20.9% 9.4% 32.3%

TABLE 13 PASI 100 at Week 48 by weight quartiles Weight CategoryGuselkumab Secukinumab Treatment Lower Upper (kg) 100 mg 300 mgDifference Limit Limit <=74 58.7% 56.1% 2.6% −10.0% 15.3% (84/143)(69/123) >74-<=87 66.4% 51.8% 14.6% 2.0% 27.2% (79/119)(73/141) >87-<=100 59.1% 47.6% 11.5% −1.4% 24.4% (78/132) (59/124) >10050.0% 38.7% 11.3% −1.4% 24.0% (70/140) (48/124)

TABLE 14 IGA 0/1 at Week 48 by weight quartiles Weight CategoryGuselkumab Secukinumab Treatment Lower Upper (kg) 100 mg 300 mgDifference Limit Limit <=74 84.6% 78.0% 6.6% −3.6% 16.7% (121/143)(96/123) >74-<=87 89.9% 78.7% 11.2% 1.8% 20.6% (107/119)(111/141) >87-<=100 83.3% 80.6% 2.7% −7.5% 12.9% (110/132)(100/124) >100 82.9% 62.9% 20.0% 8.6% 31.3% (116/140) (78/124)

TABLE 15 IGA 0 at Week 48 by weight quartiles Weight Category Guselkumab100 Secukinumab 300 Treatment Lower Upper (kg) mg mg Difference LimitLimit <=74 61.5% (88/143) 58.5% (72/123) 3.0% −9.6% 15.6% >74-<=87 71.4%(85/119) 53.9% (76/141) 17.5% 5.2% 29.9%  >87-<=100 61.4% (81/132) 50.0%(62/124) 11.4% −1.5% 24.2% >100 55.7% (78/140) 39.5% (49/124) 16.2% 3.5%28.9% Note: There were two patients in Secukinumab 300 mg group withoutbaseline weight such that Secukinumab group only has 512 patientslisted, instead of 514 patients.

TABLE 16 IGA0/1 by BMI category Treatment Lower Upper Baseline BMI Group1 Guselkumab 100 mg Secukinumab 300 mg Difference Limit Limit Normal(<25) 85.8% (115/134) 77.1% (84/109)  8.8% −1.9% 19.4% Overweight (>=25to <30) 86.9% (153/176) 81.9% (145/177) 5.0% −3.1% 13.1% Obese (>=30)83.0% (185/223) 69.3% (156/225) 13.6% 5.4% 21.9%

TABLE 17 Summary of PASI component responses at Week 48 Guselkumab 100mg Secukinumab 300 mg Full analysis set, n 534 514 Head and neck, n 499481 100% improvement, n (%) 399 (80.0) 360 (74.8) ≥90% improvement, n(%) 424 (85.0) 371 (77.1) Trunk, n 512 494 100% improvement, n (%) 432(84.4) 384 (77.7) ≥90% improvement, n (%) 444 (86.7) 395 (80.0) Upperextremities, n 532 510 100% improvement, n (%) 422 (79.3) 322 (63.1)≥90% improvement, n (%) 435 (81.8) 341 (66.9) Lower extremities, n 534513 100% improvement, n (%) 400 (74.9) 315 (61.4) ≥90% improvement, n(%) 433 (81.1) 343 (66.9)

TABLE 18 Proportion of patients achieving PASI 90 response at Week 48with guselkumab (GUS) or secukinumab (SEC) by geographic region NorthAmerica Eastern Europe Western Europe Australia Overall GUS SEC GUS SECGUS SEC GUS SEC GUS SEC 100 mg 300 mg 100 mg 300 mg 100 mg 300 mg 100 mg300 mg 100 mg 300 mg Randomized 199 192 171 167 129 119 35 36 534 514patients, n PASI 90 157 116 155 127 107 89 32 28 451 360 responders,(78.9) (60.4) (90.6) (76.0) (82.9) (74.8) (91.4) (77.8) (84.5) (70.0) n(%)

What is claimed is:
 1. A method of treating psoriasis in a patientpreviously treated with at least one dose of secukinumab, comprisingdiscontinuing secukinumab treatment to the patient; and administering anantibody to IL-23 to the patient in a clinically proven safe andclinically proven effective amount, wherein the antibody to IL-23comprises a light chain variable region and a heavy chain variableregion, said light chain variable region comprising: a complementaritydetermining region light chain 1 (CDRL1) amino acid sequence of SEQ IDNO:50; a CDRL2 amino acid sequence of SEQ ID NO:56; and a CDRL3 aminoacid sequence of SEQ ID NO:73, said heavy chain variable regioncomprising: a complementarity determining region heavy chain 1 (CDRH1)amino acid sequence of SEQ ID NO:5; a CDRH2 amino acid sequence of SEQID NO:20; and a CDRH3 amino acid sequence of SEQ ID NO:44.
 2. The methodof claim 1, wherein the patient is treated with the antibody to IL-23for at least 44 weeks to demonstrate efficacy in a psoriasis clinicalendpoint selected from the group consisting of PASI90, PASI100, IGA 0and IGA
 1. 3. The method of claim 2, wherein the psoriasis clinicalendpoint is measured 44 and/or 48 weeks after initial treatment with theantibody to IL-23.
 4. The method of claim 3, wherein the psoriasisclinical endpoint is measured 48 weeks after initial treatment with theantibody to IL-23.
 5. The method of claim 1, wherein the antibody toIL-23 is administered in an initial dose, 4 weeks after the initial doseand every 8 weeks after the dose at 4 weeks.
 6. The method of claim 1,wherein the secukinumab antibody was administered in an initial dose, 1week after the initial dose, 2 weeks after the initial dose, 3 weeksafter the initial dose, 4 weeks after the initial dose and every 4 weeksafter the dose at 4 weeks.
 7. The method of claim 1, wherein theantibody to IL-23 is administered at a dose of 100 mg.
 8. The method ofclaim 7, wherein the antibody to IL-23 is in a composition comprising100 mg/mL of antibody; 7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mML-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80of the pharmaceutical composition; wherein the diluent is water atstandard state.
 9. The method of claim 1, wherein the antibody to IL-23is safe and effective treating psoriasis at an area of a patientselected from the group consisting of scalp, nails, hands and feet. 10.The method of claim 1, further comprising administering to the patientone or more additional drugs used to treat psoriasis.
 11. The method ofclaim 10, wherein the additional drug is selected from the groupconsisting of: immunosuppressive agents, non-steroidal anti-inflammatorydrugs (NSAIDs), methotrexate (MTX), anti-B-cell surface markerantibodies, anti-CD20 antibodies, rituximab, TNF-inhibitors,corticosteroids, and co-stimulatory modifiers.
 12. The method of claim1, wherein the antibody to IL-23 is effective to reduce a symptom ofpsoriasis in the patient, induce clinical response, induce or maintainclinical remission, inhibit disease progression, or inhibit a diseasecomplication in the patient.
 13. The method of claim 1, wherein thepatient is treated for moderate to severe psoriasis.
 14. The method ofclaim 1, further comprising the step of measuring the psoriasis clinicalendpoint PASI90, PASI100, IGA 0 and/or IGA 1 at 44 and/or 48 weeks afterinitial treatment and discontinuing treatment of a patient previouslytreated with at least one dose of secukinumab and treating the patientwith guselkumab.
 15. The method of claim 1, wherein the patient haspsoriatic arthritis.
 16. A method of treating psoriasis in a patientpreviously treated with at least one dose of secukinumab, comprisingdiscontinuing secukinumab treatment to the patient; and administering anantibody to IL-23 to the patient in a clinically proven safe andclinically proven effective amount, the antibody to IL-23 comprising alight chain variable region of the amino acid sequence of SEQ ID NO: 116and a heavy chain variable region of the amino acid sequence of SEQ IDNO:
 106. 17. The method of claim 16, wherein the patient is treated withthe antibody to IL-23 for at least 44 weeks to demonstrate efficacy in apsoriasis clinical endpoint selected from the group consisting ofPASI90, PASI100, IGA 0 and IGA
 1. 18. The method of claim 17, whereinthe psoriasis clinical endpoint is measured 44 and/or 48 weeks afterinitial treatment with the antibody to IL-23.
 19. The method of claim18, wherein the psoriasis clinical endpoint is measured 48 weeks afterinitial treatment with the antibody to IL-23.
 20. The method of claim16, wherein the antibody to IL-23 is administered in an initial dose, 4weeks after the initial dose and every 8 weeks after the dose at 4weeks.
 21. The method of claim 16, wherein the secukinumab antibody wasadministered in an initial dose, 1 week after the initial dose, 2 weeksafter the initial dose, 3 weeks after the initial dose, 4 weeks afterthe initial dose and every 4 weeks after the dose at 4 weeks.
 22. Themethod of claim 16, wherein the antibody to IL-23 is administered at adose of 100 mg.
 23. The method of claim 22, wherein the antibody toIL-23 is in a composition comprising 100 mg/mL of antibody; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.
 24. Themethod of claim 16, wherein the antibody to IL-23 is safe and effectivetreating psoriasis at an area of a patient selected from the groupconsisting of scalp, nails, hands and feet.
 25. The method of claim 16,further comprising administering to the patient one or more additionaldrugs used to treat psoriasis.
 26. The method of claim 25, wherein theadditional drug is selected from the group consisting of:immunosuppressive agents, non-steroidal anti-inflammatory drugs(NSAIDs), methotrexate (MTX), anti-B-cell surface marker antibodies,anti-CD20 antibodies, rituximab, TNF-inhibitors, corticosteroids, andco-stimulatory modifiers.
 27. The method of claim 16, wherein theantibody to IL-23 is effective to reduce a symptom of psoriasis in thepatient, induce clinical response, induce or maintain clinicalremission, inhibit disease progression, or inhibit a diseasecomplication in the patient.
 28. The method of claim 16, wherein thepatient is treated for moderate to severe psoriasis.
 29. The method ofclaim 16, further comprising the step of measuring the psoriasisclinical endpoint PASI90, PASI100, IGA 0 and/or IGA 1 at 44 and/or 48weeks after initial treatment and discontinuing treatment of a patientpreviously treated with at least one dose of secukinumab and treatingthe patient with guselkumab.
 30. The method of claim 16, wherein thepatient has psoriatic arthritis.
 31. A method of treatingmoderate-to-severe plaque psoriasis in an adult patient who is acandidate for systemic therapy or phototherapy and who has previouslybeen treated with at least one dose of secukinumab, comprisingdiscontinuing secukinumab treatment to the patient; and administering anantibody to IL-23 to the patient in a clinically proven safe andclinically proven effective amount, wherein the antibody comprises alight chain variable region of the amino acid sequence of SEQ ID NO: 116and a heavy chain variable region of the amino acid sequence of SEQ IDNO: 106, the dosage is 100 mg administered by subcutaneous injection atWeek 0, Week 4 and every 8 weeks thereafter and the antibody is at aconcentration of 100 mg/mL in a single-dose prefilled syringe comprising7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mM L-Histidinemonohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80 and thediluent is water at standard state.